Trend Analysis of A Database of Intravenous Pharmacokinetic Parameters in Humans For 670 Drug Compounds

DMD Fast Forward. Published on April 21, 2008 as DOI: 10.1124/dmd.108.
020479
DMD This
Fastarticle
Forward. Published
has not been copyedited on April 21,The
and formatted. 2008
final as doi:10.1124/dmd.108.020479
version may differ from this version.
DMD #20479
TREND ANALYSIS OF A DATABASE OF INTRAVENOUS

PHARMACOKINETIC PARAMETERS IN HUMANS FOR 670 DRUG
COMPOUNDS
R. Scott Obach†, Franco Lombardo,*§ Nigel J. Waters#
Pharmacokinetics Dynamics and Metabolism, Pfizer Global Research and Development,

Groton Laboratories, Groton, CT 06340 and Metabolism and Pharmacokinetics Groups
Novartis Institutes for Biomedical Research, Cambridge, MA 02139 and Horsham, West
Sussex RH12 5AB, United Kingdom.
Downloaded from dmd.aspetjournals.org at ASPET Journals on May 10, 2016

RSO: Pharmacokinetics Dynamics and Metabolism, Pfizer Global Research and
Development, Groton Laboratories.
FL: Metabolism and Pharmacokinetics Group, Novartis Institutes for Biomedical
Research, Cambridge.
NJW: Metabolism and Pharmacokinetics Group, Novartis Institutes for Biomedical
Research, Horsham.
Copyright 2008 by the American Society for Pharmacology and Experimental Therapeutics.
DMD Fast Forward. Published on April 21, 2008 as DOI: 10.1124/dmd.108.020479
This article has not been copyedited and formatted. The final version may differ from this version.
DMD #20479
TREND ANALYSIS OF PHARMACOKINETIC PARAMETERS IN HUMANS
Address correspondence to: Franco Lombardo, Novartis Institutes for Biomedical

Research, Bldg. 600, 1B-123, 250 Massachusetts Avenue, Cambridge MA, 02139. Phone
(617) 871-4003; Fax: (617) 871-3078; e-mail: franco.lombardo@novartis.com.
Text pages:21
Tables: 3
Figures: 10
References : 33
Words in Abstract: 183

Words in Introduction: 562
Words in Discussion: 1833
Non-standard abbreviations:
PSA = Polar Surface Area
2
DMD #20479
Abstract
We present herein a compilation and trend analysis of human intravenous
pharmacokinetic data on 670 drugs representing, to our knowledge, the largest publicly
available set of human clinical pharmacokinetic data. This dataset provides the drug
metabolism scientist with a robust and accurate resource suitable for a number of
applications including: in silico modelling, in vitro – in vivo scaling, and physiologically-
based pharmacokinetic approaches. Clearance, volume of distribution at steady state,

mean residence time, and terminal phase half-life were obtained or derived from original
references exclusively from studies utilizing intravenous administration. Plasma protein
binding data were collected from other sources to supplement these pharmacokinetic
data. These parameters were analyzed concurrently with a range of simple
physicochemical descriptors and resultant trends and patterns within the data are
presented. Our findings with this much expanded dataset were consistent with earlier
described notions of trends between physicochemical properties and pharmacokinetic
behavior. These observations and analyses, along with the large database of human
pharmacokinetic data, should enable future efforts aimed toward developing quantitative
structure-pharmacokinetic relationships and improving our understanding of the
relationship between fundamental chemical characteristics and drug disposition.
3
DMD #20479
The prediction of human pharmacokinetics for new compounds has become an
important process in drug research. Previous reports have focused on prediction methods
that utilize animal pharmacokinetic data (Ward and Smith, 2004a; Ward and Smith,
2004b; Caldwell et al., 2004; Jolivette and Ward, 2005; Evans et al., 2006; Mahmood et
al., 2006; Martinez et al., 2006; Tang and Mayersohn, 2006; McGinnity et al., 2007;
Fagerholm, 2007) as well as in vitro data (Obach et al., 1997; Lombardo et al., 2002;

Nestorov et al., 2002; Lombardo et al., 2004; Riley et al., 2005; Grime and Riley, 2006).
Recently, the availability of computational chemistry methodologies has increased and
these have been applied to the prediction of human pharmacokinetics and/or general
ADMET properties (Cruciani et al., 2005; Gleeson et al., 2006; Ghafourian et al., 2006;
Lombardo et al., 2006; Gunturi and Narayanan, 2007; Norinder and Bergstroem, 2007;
Gleeson, 2007). The construction of effective models not only requires sound
computational tools but, very importantly, databases that have been carefully assembled.
Human pharmacokinetic databases are challenging to compile because each data point
typically derives from a separate report in which experimental approaches differ from
report to report. Such variables include the numbers and types of study subjects (e.g.
healthy vs. diseased, gender, age, etc), the routes of administration and doses, sample
collection times, methods of analysis of the samples, and the types of pharmacokinetic
parameters reported.
To develop computational models for the prediction of human clearance (CL),
volume of distribution (VD), and absolute oral bioavailability, it is essential that data
used in model training sets are obtained from studies in which the dose was administered
4
DMD #20479
intravenously. It is also important that the methods of calculations for reported
pharmacokinetic parameters be done consistently. (For example, values reported
generally as VD can vary from report to report and include central VD, terminal phase
VD, or steady-state VD.) The fairly large set of human pharmacokinetic data reported in
Appendix II of the famous textbook “The Pharmacological Basis of Therapeutics”
(Goodman and Gilman, 2006) has been frequently cited as a source of data for
computational model construction. However, it is important to note that this dataset was

primarily intended for health care professionals and medical students to understand the
pharmacokinetic basis for dosing regimens of frequently used drugs, rather than used for
the development of structure-pharmacokinetic relationships. Hence, many of the
pharmacokinetic parameters reported are derived from oral administration and many of
the VD values reported include terminal phase VD. This can confound the performance
of models.
The objectives of this study were two-fold: (1) Develop an exhaustive database
of human pharmacokinetic parameters exclusively from intravenous administration, that
can be used by scientists involved in early drug research in the construction of models for
predicting pharmacokinetic parameters for new compounds; and (2) From this dataset,
gain some initial insight into the relationships between chemical properties derived from
structural attributes to human pharmacokinetic parameters. To the first objective, we
have carefully and exhaustively mined the scientific literature for the human
pharmacokinetic parameters CLp, VDss, MRT, and t1/2 measured after intravenous
administration. We successfully obtained human intravenous pharmacokinetic data for
670 compounds, which, to our knowledge, represents the largest database of this type.
5
DMD #20479
We have also included plasma protein binding data for most of these compounds. This
database is reported herein and also provided in tabular format as supplemental
information that can be downloaded from the website of this journal. As such, it can be
of use to scientists seeking to develop computational models and correlative approaches
to the prediction of human pharmacokinetics of new compounds. For the second
objective, we have examined the relationships between human intravenous
pharmacokinetic parameters (VDss VDss,u, CLp, CLp,u, MRT, t1/2, and fu) and various

computed fundamental physico-chemical parameters (e.g. logP, charge, etc.) using this
database. The trends observed can be instructive to those engaged in the design of new
drugs. The knowledge that can be gained by utilizing this large database in model
construction should be of considerable use to scientists involved in the discovery of new
drugs.
6
DMD #20479
Methods
Collection and Selection of Data for the Database. Pharmacokinetic data are reported in
a large array of manners. Various units and symbols are used, some reports utilize
compartmental analysis while others use a non-compartmental approach, and the level of
detail describing the conduct of the study included in the methods sections can vary
considerably. This requires very careful scrutiny when mining these data for
fundamental pharmacokinetic parameters. The pharmacokinetic data included in this

database are strictly from intravenous administration. There are no data included from
oral, intramuscular, or any other dosing routes. Intravenous data were from rapid bolus
injection or infusions.
Of the pharmacokinetic parameters that were gathered for this database, the one
that varied the most and required the most attention to how it was determined is the
volume of distribution. For this database, we sought the steady-state volume of
distribution (VDss) since this volume term describes the overall distributional behavior
most generally. However, many authors of pharmacokinetic studies report only the
terminal phase volume of distribution and many others report volume of distribution
without denoting whether it was the terminal phase VD, the central VD, or the steady-
state VD. Thus, the preference for papers selected for inclusion in this database
specifically reported VDss. When the usage of the VD term was vague (i.e. lacking the
subscript designating the value as VDss or another VD), but a clear description of the
pharmacokinetic calculations were included and indicated that the term was in fact VDss,
the value was included. In other papers, micro constants from compartmental analysis
were reported without including VDss. In these cases, the rate constants and the reported
7
DMD #20479
central volume of distribution were used to calculate VDss using one or the other of the
following equations depending upon what was reported:
 k12 
VDss = VD c • 1 + 
 k 21 
VDc refers to the volume of the central compartment, and was sometimes called V1, VP,
or V0 in the reports. In other compartmental models, more micro rate constants were
derived from the fit of the data, requiring an expansion of the equation:

 k 12 k 13 
VD ss = VD c • 1 + + 
 k 21 k 31 
In other cases, the compartmental parameters were reported. If VDss was not included in
the paper, then the equation:
 A B 
Dose •  + 
α β
2 2

VD ss = 2
A B
 + 
α β 
was used to calculate VDss. In a few papers, pharmacokinetic parameters were not
reported, but plasma concentration vs time data were listed. In these cases, VDss was
calculated using the standard equation using mean plasma concentration vs time data:
Dose • AUMC 0-∞

VD ss =
(AUC 0-∞ )2
In some cases, a drug had neither the VDss reported per se nor did it have compartmental
parameters reported that could be used to calculate VDss, in any description of its
pharmacokinetics. In these instances, plots of plasma concentration vs. time included in
the report were digitized and the resulting concentration vs. time data were subjected to
non-compartmental analysis. This was only done if there were no other reports on the
8
DMD #20479
same drug that had reported VDss values. In some cases, the only references containing
pharmacokinetic values were review articles in which the cited original research data
were not available. If the VD values listed in these articles were clearly stated to derive
from intravenous administration and if they were specifically described as steady-state
VD values these values were used. Product labels, in which the data listed have been
reviewed and approved by the U.S. Food and Drug Administration, were sometimes the
only source of VDss data. In these cases, since these had been subjected to a

governmental regulatory review, they were included in this database even though the
original methods and results that yielded the data are not included in the product label.
From the sources that possessed adequate VDss data, could have VDss calculated
from compartmental parameters, or could have VDss calculated from digitized plots, the
values of plasma clearance and half-life were also obtained. Parameters (CL, VDss) that
were already corrected for body weight were included as is. If they were not reported in
this manner, then they were converted using the mean body weight of the subjects listed
in the report. If only a range of body weights were included in the report, then the
midpoint value was used for weight. In cases where no body weight information was
included, a value of 70 kg was assumed. For those reports in which the parameters were
corrected for body surface area, a conversion of 1.73 m2 to 70 kg was generally assumed.
The pharmacokinetic data were preferably obtained from reports in which healthy
young adult subjects were studied, or patient populations in which health or physiological
condition is not severely compromised such that there would be reason to believe that
that pharmacokinetics in the patients would be different from healthy subjects (e.g.
elderly subjects, obese subjects, etc). In some instances, data were only available from
9
DMD #20479
patient populations and/or populations taking concomitant medications (e.g. cancer
drugs) and in these instances, the data were included. In many cases, reports of
pharmacokinetic data were made with the intent to compare different populations,
especially drug-drug interaction studies and studies comparing healthy individuals to
those with either hepatic or renal dysfunction. In these cases, the pharmacokinetic data
were only from the study groups that were used as the controls for comparison (the
healthy group in hepatic or renal dysfunction studies or the groups not receiving a second

drug in drug interaction studies). Another source of intravenous pharmacokinetic data
were studies in which the objective was the determination of the absolute oral
bioavailability. In these instances, the pharmacokinetic parameters from the intravenous
part of the study were used. Values were reported to two significant digits, and data were
rounded from those reports in which the values were reported to greater than two digits.
Finally, when multiple studies within a report and/or different reports were used, the data
were weight-averaged by number of subjects.
For compounds possessing adequate intravenous pharmacokinetic data, the
corresponding protein binding values in human plasma (or serum) were searched. In all
cases, original research reports containing these values were sought but protein binding
data were included even in those cases where the original methods and results were not
present (e.g. product labels, review articles). We then calculated the logK as the
logarithm of the ratio bound/free using the fu data reported. However, in many instances,
no published protein binding data could be found.
10
DMD #20479
The physicochemical parameters calculated for all compounds and described in
the Results sections were extracted from the table available for each compound through
SciFinder (2007), generated via version 8.14 of the ACDLabs software.
11
DMD #20479
Results
Characteristics of the Pharmacokinetic and Physicochemical Values. Through extensive
mining of the scientific literature and in some cases reanalysis of concentration vs. time
data, the human intravenous pharmacokinetic parameters VDss, CL, MRT, and t1/2, were
found or calculated for 670 compounds. In addition, human plasma protein binding
values were obtained for 554 of the 670 compounds. These data are listed in Table 1, and
a spreadsheet containing these values along with the literature references is included as
an attachment in the Supporting Information. The data span over considerable ranges

(Figure 1). Volume of distribution at steady-state ranged from a low of 0.035 L/kg to 700
L/kg, for indocyanine green and hydroxychloroquine, respectively. The vast majority
(90%) reside in a 100-fold range between 0.1 and 10 L/kg, with mean and median values
of 4.2 and 0.96 L/kg, respectively. Forty-one percent of the compounds have VDss values
less than 0.7 L/kg (Table 2), a value generally accepted as representative of total body
water. Eight percent of compounds had VDss values greater than 10 L/kg, indicating an
extensive level of tissue partitioning.
Plasma clearance values ranged from 0.0037 (7-hydroxystaurosporine) to 1070
(artesunate) mL/min/kg (Figure 1), with mean and median values of 10 and 4.0
mL/min/kg, respectively. Approximately three-fifths of the compounds resided in a
range between 1 and 10 mL/min/kg, with 16% possessing clearance values below 1
mL/min/kg (very low clearance). Fifty-six of the compounds had CL values greater than
liver blood flow (Table 2), suggesting the possibility of extrahepatic clearance
mechanisms in these cases, or blood-to-plasma ratios in excess of unity. Many of the
compounds possessing high CL values are agents like anaesthetics, pain medications, or
cytotoxic cancer chemotherapeutics, which are drug classes that are frequently
12
DMD #20479
administered via the intravenous route to optimize therapy or use, and other high CL
compounds are prodrugs or drugs in which pharmacologically active metabolites are
responsible for the bulk of the effect (e.g. dolasetron, esmolol, etc).
Terminal phase half-life values ranged from 4 min (indocyanine green) to 50 days
(suramin) (Figure 1), with two thirds residing between 1 and 12 hr (Table 2). (Half-lives
for the bisphosphonate class of drugs may be underestimated since they sequester into
bone, but may not be detectable in the systemic circulation.) The average t1/2 was 18 hr
and the median value was 4.1 hr. Since half-life is derived from CL and VD, it cannot be

directly related to physiological properties such as hepatic blood flow or volume of total
body water. Half-life values can be partitioned into zones loosely based on dosing
regimen frequency values (provided that there is not a considerable difference between
pharmacokinetics and pharmacodynamics), and it is a common practice in
pharmaceutical research to seek drugs that would be amenable to convenient q.d. dosing
regimens. However, based on this, over three quarters of compounds would likely
require dosing greater than once-per-day since they have t1/2 values below 12 hr (Table
2). This same conclusion could be drawn if MRT were used to address this question.
Interestingly, a plot of MRT versus CL (Figure 2) shows a clustering of datapoints which
implies that in order to obtain a MRT of at least 5 h for an acidic drug a CL value lower
than 0.5 mL/min/kg is required; a consequence of the low VDss for acidic compounds.
The ranking of protein binding values is in Figure 1. The values ranged between
no binding (several compounds) and 99.98% bound (amiodarone), with mean and median
free fractions of 0.38 and 0.26, respectively. Two-thirds of the compounds in the set are
less than 90% bound, and about one-eighth could be considered highly bound (> 99%;
Table 2).
13
DMD #20479
The 670 compounds in this dataset span a wide range of fundamental physico-
chemical characteristics (Figure 3). The typical drug-like space for molecular weight
(200 to 600 Da) is represented by 80% of the compounds, with median value of 342 Da
and a range from 3 (lithium) to 1816 (dalbavancin). The median value for polar surface
area (PSA) was 87 Å2. The set encompasses 159 acids, 271 bases, 173 neutral
compounds, and 67 zwitterions (Figure 3). These were categorized with a cutoff value of
10% ionized (anionic for acids; cationic for bases, both for zwitterions) at pH 7, using the
calculated pKa values from ACD labs. Lipophilicity, as described by clogP and clogD7.0

had median values of 1.92 and 0.42, respectively The median values for numbers of
rotatable bonds, hydrogen bond acceptors, and hydrogen bond donors were 5, 6, and 2,
respectively. It can be noted that, even though these data were derived from
intravenously dosed compounds, the median values for logP as well as for the number of
hydrogen bond acceptors and hydrogen bond donors were well below the limits set by the
Lipinski “rule of 5” (Lipinski et al., 1997) as perhaps may be expected for compounds
either marketed or in clinical development. Furthermore, the number of rotatable bonds
was below the limit reported by Veber (Veber et al., 2002) for permeable compounds.
Trends in the Dataset: VDss vs Physicochemical Properties. The dataset was mined for
any trends between the physicochemical values obtained and the human VDss values. In
no case was there a relationship such that any single physicochemical property could be
considered uniquely predictive of VDss, nevertheless there were trends in the data
suggesting a significant contribution of some physicochemical properties to VDss.
Trends could not be easily observed when values were partitioned by means, because of
the scatter and overlap in the data (as exemplified in Figure 4B), however trends could be
observed for median values. Median VDss values showed trends with clogP, PSA, and
14
DMD #20479
number of H-bond acceptors and donors (Figure 4), as well as charge type (Table 3).
These four properties have varying extents of inter-relatedness. The properties of high
polar surface area, high numbers of H-bond acceptors/donors, and low lipophilicity tend
to reside in similar sets of molecules, and median VDss values trend higher for low PSA,
low numbers of H-bond acceptors/donors, and high lipophilicity (Figure 4). Negative
charge (acids) have lower median and mean VDss values than bases, with neutral
molecules and zwitterions in between (Table 3). The median values of VDss for the acids
remain around 0.2 L/kg irrespective of clogP, whereas for bases, neutrals and zwitterions

there is an upward trend observed for VDss with increasing lipophilicity (Figure 5).
Data were also examined after correcting VDss for free fraction (i.e. free VDss =
VDss/fu), which is more indicative of the extent of tissue partitioning. As with total VDss,
trends for free VDss were observed primarily through examination of median values since
there is considerable scatter among the data. The same four physicochemical parameters,
lipophilicity, PSA, charge type, and sum of hydrogen bond donors and acceptors appear
to be the properties that contribute to free VDss (Figure 6). An interesting trend emerged
when the relationship between VDss and lipophilicity was stratified by charge type; a
considerable improvement was observed when the trend was examined for free VDss than
for total VDss (Figure 5). For example, there was no trend in the relationship between
VDss and lipophilicity for acids, but when examined for free VDss, there was a trend that
increasing lipophilicity leads to greater free VDss values. This tends to indicate that
plasma protein binding dominates in the distribution of negatively charged compounds.
Trends in the Dataset: CL vs Physicochemical Properties. Similar to the observations
with VDss, readily discernable trends could be observed between some physicochemical
properties and CL, however no relationship was tight enough to suggest that any single
15
DMD #20479
property could be quantitatively predictive of CL. Decreases in median CL were
observed with increases in PSA or sum of hydrogen bond acceptors and donors (Figure
7). Only a weak trend could be observed between median CL and lipophilicity. Bases
had generally greater CL values than acids, neutrals, or zwitterions (Figure 7). The
relationship between lipophilicity and median CL was considerably strengthened when
CL values were converted to free CL values (Figures 8 and 9). Interestingly, unlike the
median CL values, the difference in median free CL values for acids, bases, and neutrals
was not observable (Table 3). When CL values were examined for any relationship to

lipophilicity after stratification by charge type, no apparent trends could be observed, but
when corrected for protein binding (i.e. free CL = CL/fu), the relationship showed a weak
trend with free CL increasing with increasing lipophilicity (Figure 9).
Trends in the Dataset: Protein Binding vs Physicochemical Properties. Of the physico-
chemical properties examined, relationships were only observed between protein binding
and lipophilicity and charge type (Figure 10). With greater lipophilicity, protein binding
tends to increase, and this trend becomes apparent for all charge types when protein
binding is expressed as the logarithm of the apparent affinity constant, logK (or
log[bound/free]) as shown in Figure 10.
16
DMD #20479
Discussion
The utility of human pharmacokinetic databases in the development of a greater
understanding of the relationship between chemical structure and pharmacokinetic
behavior is unquestionable. Over the years, trends have been noted in the relationship
between PK and structure (and physicochemical properties), but these have been for
limited compound sets, in many cases within a single class of drugs (Smith, 1997; van de
Waterbeemd et al., 2001). In this report, we have gathered a database of human
pharmacokinetic parameters of a size never before assembled. Each value was obtained

after careful analysis of original scientific literature (or in a few cases from drug product
labels approved by government regulatory authorities). In many cases, different
investigators chose to analyze data and report pharmacokinetic parameters in different
manners (e.g. non-compartmental vs compartmental analysis; VDss vs VDβ, intravenous
vs oral dosing, etc). Thus, we reviewed each original report to ensure that the parameters
reported were consistent from compound to compound, and if not, to reanalyze the data
to obtain the desired parameters. Unlike other commonly cited pharmacokinetic
databases (Goodman and Gilman, 2006), the database values presented in this report are
exclusively from studies in which drugs were administered intravenously. Thus, these
values are not confounded by effects of slow and incomplete absorption or extensive
first-pass extraction. The database is offered as a supplemental file to this report, so that
other scientists can easily download it and use it to test various hypotheses and develop
Quantitative Structure PharmacoKinetic Relationships models. However, the following
limitations of this database should be appreciated: (1) study designs vary from drug to
drug with regard to dose level, number of subjects, blood sampling times, analytical
procedures, etc; (2) values reported are means and do not account for inter-subject
17
DMD #20479
variability. Nevertheless, the database should be able to be used to provide insight into
the relationship between structure and pharmacokinetics and useful in building
computational models. Efforts on the latter are underway and a discussion of initial
efforts on the former are described below.
The set of compounds reported in this trend analysis encompasses a wide variety
of structures and therapeutic areas as well as physicochemical properties as shown in the
Results section, and Table 2 shows the pharmacokinetics parameters grouped according
to defined thresholds. For VDss a large proportion of the values (approximately 42 %)

falls within total body water (0.7 L/kg). Only a small subset of these drugs was confined
to blood (or plasma) volume, with a value close to the generally accepted distribution
volume of albumin, or 0.1 L/kg (McGinnity et al., 2007). (The latter can be approximated
to the above value, from the extravascular:intravascular ratio, or RE/I, of 1.4, as in the
Øie-Tozer equation (Øie and Tozer, 1979) assuming a blood volume of 0.07 L/kg.) That
would indicate that while most of these compounds do not extensively partition into
tissues they can distribute throughout bodily fluids and, therefore, may be considered
unbound in tissues and potentially capable to reach the intended target. If a volume of 0.7
L/kg is taken as the threshold for total body water, about 60% of the compounds have
values exceeding that threshold, with almost one-half of these compounds (29% of total)
having volumes in excess of 2 L/kg. These compounds may be expected to partition
moderately to extensively into tissues and contribute significantly to the residence time
(or t1/2) of the drug. However, no direct correlation can be drawn between VDss values
and the ability of a compound to reach the intended pharmacological target, or to diffuse
into a particular organ, since these values are overall “averages” across all tissues and
fluids.
18
DMD #20479
Overall, nearly 85% of the compounds reside in the moderate to low range (< 15
mL/min/kg, or hepatic extraction ratio EH approximately taken as ≤ 0.7) of clearance
which, in conjunction with a moderate to high volume of distribution, might contribute to
yielding a fairly large residence or terminal half-life, since a good proportion of
compounds reside in ranges of volume of distribution that exceed total body water.
Nevertheless, only a minority of compounds, about 20%, have a t½ profile consistent with
a once-a-day dosage regimen, and about one-half show a half-life equal to or lower than 4
hours. A very significant proportion, about one-third, show an intermediate half-life

which would still be generally considered unsuitable for a once-a-day dosage (barring
non-direct PK/PD relationships or tolerance to a high Cmax/Ceff ratio). However,
depending on the therapeutic target, a rapid onset and short half-life may be desirable and
a once-a-day dosing regimen may not always be needed especially for acute therapy.
Conversely, absorption kinetics may be such that t1/2 via the oral route exceeds that
following iv administration, permitting once-a-day dosage regimens.
Physicochemical properties and their impact on drug metabolism and
pharmacokinetics is a broad and complex topic. Unfortunately, there is no single unifying
descriptor which is able to explain drug pharmacokinetic behavior. The rule-of-5 concept
developed by Lipinski et al. (Lipinski et al., 1997) utilizes thresholds of logP, molecular
weight, hydrogen bond acceptors and hydrogen bond donors to classify oral drug
absorption. However, with respect to other PK parameters typically two key descriptors,
lipophilicity (expressed as logP or logD) and charge/ionization type, have been employed
with general trends observed in certain drug classes (Smith, 1997; van de Waterbeemd et
al., 2001). Lipophilicity effectively models a number of partitioning and distribution
processes including cell membrane permeation, membrane and protein binding, affinity
19
DMD #20479
for drug-metabolizing enzymes, while charge type reflects ion-pair interactions with
plasma proteins, membrane lipids and specific drug-metabolizing enzymes.
Plasma protein binding typically shows a sigmoidal relationship with lipophilicity as
demonstrated by van de Waterbeemd et al. (van de Waterbeemd et al., 2001) on a dataset
of ~ 150 acidic, basic and neutral compounds. When expressed as the logarithm of the
apparent affinity constant (logK) this sigmoidal trend becomes linear and is exemplified
in the dataset of 554 compounds presented here (Figure 10). Increasing lipophilicity
typically yields increased protein binding as the interaction with albumin and α1-acid

glycoprotein is driven by hydrophobic forces. Acidic compounds show correspondingly
higher binding relative to bases and neutrals due to an ion-pair interaction with a basic
residue within albumin (Ghuman et al., 2005). Basic compounds tend to show high
affinity for α1-acid glycoprotein due to an electrostatic interaction with acidic residues
(Kremer et al., 1988). Overall, plasma protein binding influences the disposition profile
in terms of both CL and VDss as only free drug is available for elimination and
distribution into peripheral tissues. By converting CL and VDss into their free forms, the
confounding impact of plasma protein binding, and the physicochemistry which drives it,
was removed. This led to much improved trends between physicochemical properties and
free CL and VDss.
In a physiological sense, steady-state volume of distribution can be described by
the Gillette or Øie-Tozer equations (Øie and Tozer, 1979), where the weighted mean ratio
of plasma binding to tissue binding is the crucial term. Factors driving the unbound
fraction in plasma are as described above, while the unbound fraction in tissue is
dependent on cell membrane permeability and non-specific hydrophobic interaction with
cellular lipids and protein. In addition, bases typically exhibit an ion-pair interaction with
20
DMD #20479
the charged polar head group of membrane phospholipids contributing to an increased
tissue affinity and therefore VDss. Furthermore, basic compounds have the potential for
specific interaction with subcellular organelles such as lysosomes and mitochondria
through a pH partition mechanism, as illustrated by some of the psychotropic drugs
(Daniel and Wojcikowski, 1997). The lipophilic and charge dependence of tissue affinity
has been nicely demonstrated in correlations of free VDss and logD on small compound
datasets (Smith, 1997; van de Waterbeemd et al., 2001) corroborating our findings with
670 compounds. Additionally, we observed a trend with polar surface area and numbers

of hydrogen bond donors and hydrogen bond acceptors; increasing polarity leads to a
reduction in the median VDss. These polarity descriptors, to some extent inversely related
to lipophilicity, demonstrate that VDss cannot be explained by logP and charge type alone
and highlight the utility of multivariate in silico approaches to VDss prediction (Gleeson
et al., 2006; Lombardo et al., 2006). The magnitude of this dataset may now allow
exploration of specific functional moieties or substituents that play an integral role in
tissue distribution and VDss.
Mammals have evolved a number of clearance mechanisms designed to render
lipophilic xenobiotics more water soluble to allow efficient renal or biliary elimination.
Introducing hydrophilicity into xenobiotics is typically a concerted effort of
functionalization and conjugative metabolic reactions, mediated by cytochromes P450
and UDP-glucuronosyl transferases or sulfotransferases, respectively. The Km for P450
reactions is inversely related to lipophilicity as the binding of substrate to enzyme relies
on hydrophobic interactions (Lewis and Dickins, 2003). Positive correlations of free
metabolic clearance and logD support this finding, being irrespective of charge type
(Smith, 1997). We observed a general trend of increasing free CL with logP, supporting
21
DMD #20479
earlier work with this much expanded dataset. The variation within this trend contains
latent information not described solely by lipophilicity. Renal CL, for example, is
typically inversely correlated with partition or distribution coefficients, as increasing
lipophilicity allows efficient tubular passive reabsorption in the nephron of the kidney.
Trends with polarity descriptors (hydrogen bond donors/acceptors and PSA) were also
observed such that median CL decreases as polarity is amplified, in line with established
reasoning on metabolic CL SAR. Latent information within the global trend of logP and
CL also concerns functionality and substituent effects on CL. One such example is the N-

dealkylation of the benzodiazepines; clonazepam, oxazepam, diazepam and temazepam,
where differences in CL are related to the propensity of N-demethylation and not bulk
lipophilicity (Smith, 1997). These examples of functionalization effects should be well
represented in this 670 compound dataset and provide an opportunity for further
exploration.
Future efforts are directed at the utilization of this dataset in gaining a better
understanding of the relationship between chemical structure and pharmacokinetic
behavior. While the analysis in this report focused on gross physicochemical properties
such as lipophilicity and charge, further questions can be asked regarding the impact of
specific chemical substituents on human pharmacokinetic parameters and, potentially,
lead to structure-property relationships. In particular the exploration of the predictability
of clearance and half-life using in silico, in vitro-in vivo or in vivo correlative methods
could be attempted using this large and accurate dataset of human data. Volume of
distribution, as an example, may be more related to overall physicochemical properties
which would explain the previous successes in model building for this parameter(Gleeson
22
DMD #20479
et al., 2006; Lombardo et al., 2006), while clearance may have a greater dependence on
specific chemical substituents.
Efforts are now underway, by our groups, to use these data to further our
understanding of the complex relationships between structure and PK parameters, using
several approaches along the lines described above. This large set of carefully compiled
human PK data and the basic structure-PK relationships observed thus far should be of
use in the design of new medicines.

Acknowledgements. We wish to thank our NIBR Cambridge colleagues, Drs. S.
Harriman and G. Liang, Mr. A. Amaral, Mr. M. Gunduz and Ms. J. Zhan for searching
and providing some of the PK data reported.
23
DMD #20479
References
Caldwell GW, Masucci JA, Yan Z and Hageman W (2004) Allometric scaling of
pharmacokinetic parameters in drug discovery: Can human CL, Vss and t1/2 be predicted
from in-vivo rat data? Eur J Drug Metab Pharmacokinet 29:133-143.
Cruciani G, Carosati E, De Boeck B, Ethirajulu K, Mackie C, Howe T and Vianello R
(2005) MetaSite: Understanding metabolism in human cytochromes from the
perspective of the chemist. J Med Chem 48:6970-6979.

Daniel WA and Wojcikowski J (1997) Contribution of lysosomal trapping to the total
tissue uptake of psychotropic drugs. Pharmacol Toxicol 80:62-68.
Evans CA, Jolivette LJ, Nagilla R and Ward KW (2006) Extrapolation of preclinical
pharmacokinetics and molecular feature analysis of "discovery-like" molecules to predict
human pharmacokinetics. Drug Metab Dispos 34:1255-1265.
Fagerholm U (2007) Prediction of human pharmacokinetics - evaluation of methods for
prediction of volume of distribution. J Pharm Pharmacol 59:1181-90.
Ghafourian T, Barzegar-Jalali M, Dastmalchi S, Khavari-Khorasani T, Hakimiha N and
Nokhodchi A (2006) QSPR models for the prediction of apparent volume of distribution.
Int J Pharm 319:82-97.
24
DMD #20479
Ghuman J, Zunszain PA, Petitpas I, Bhattacharya AA, Otagiri M and Curry S (2005)
Structural basis of the drug binding specificity of human serum albumin. J Mol Biol
353:38-52.
Gleeson MP, Waters NJ, Paine SW and Davis AM (2006) In silico human and rat Vss
quantitative structure-activity relationship models. J Med Chem 49:1953-1963.
Gleeson MP (2007) Plasma protein binding affinity and its relationship to molecular

structure: An in-silico analysis. J Med Chem 50:101-112.
Goodman LS and Gilman A (2006) The Pharmacological Basis of Therapeutics, 11th ed.
McGraw-Hill Publishers, New York.
Grime K and Riley RJ (2006) The impact of in vitro binding on in vitro-in vivo
extrapolations, projections of metabolic clearance and clinical drug-drug interactions.
Curr Drug Metab 7:251-64.
Gunturi SB and Narayanan R (2007) In silico ADME modeling 3: computational
models to predict human intestinal absorption using sphere exclusion and kNN QSAR
methods. QSAR Combinat Sci 26:653-668.
Jolivette LJ and Ward KW (2005) Extrapolation of human pharmacokinetic parameters
from rat, dog, and monkey data: Molecular properties associated with extrapolative
success or failure. J Pharm Sci 94:1467-1483.
25
DMD #20479
Kremer JMH, Wilting J and Janssen LHM (1988) Drug binding to human alpha-1-acid
glycoprotein in health and disease. Pharmacol Rev 40:1-47.
Lewis DFV and Dickins M (2003) Baseline lipophilicity relationships in human
cytochromes P450 associated with drug metabolism. Drug Metab Rev 35:1-18.
Lipinski CA, Lombardo F, Dominy BW and Feeney PJ (1997) Experimental and

computational approaches to estimate solubility and permeability in drug discovery and
development settings. Adv Drug Deliv Rev 23:3-25.
Lombardo F, Obach RS, Shalaeva MY and Gao F (2002) Prediction of volume of
distribution values in humans for neutral and basic drugs using physicochemical
measurements and plasma protein binding data. J Med Chem 45:2867-2876.
Lombardo F, Obach RS, Shalaeva MY and Gao F (2004) Prediction of human volume of
distribution values for neutral and basic drugs. 2. Extended data set and leave-class-out
statistics. J Med Chem 47:1242-1250.
Lombardo F, Obach RS, DiCapua FM, Bakken G, Lu J, Potter DM, Gao F, Miller MD
and Zhang Y (2006) A hybrid mixture discriminant analysis-random forest computational
model for the prediction of volume of distribution in human. J Med Chem 49:2262-2267.
26
DMD #20479
Mahmood I, Martinez M and Hunter RP (2006) Interspecies allometric scaling. Part I:
prediction of clearance in large animals. J Vet Pharmacol Therapeut 29:415-423.
Martinez M, Mahmood I and Hunter RP (2006) Interspecies allometric scaling:
prediction of clearance in large animal species: part II: mathematical considerations. J
Vet Pharmacol Therapeut 29:425-432.
McGinnity DF, Collington J, Austin RP and Riley RJ (2007) Evaluation of human

pharmacokinetics, therapeutic dose and exposure predictions using marketed oral drugs.
Curr Drug Metab 8:463-479.
Nestorov I, Gueorguieva I, Jones HM, Houston B and Rowland M (2002) Incorporating
measures of variability and uncertainty into the prediction of in vivo hepatic clearance
from in vitro data. Drug Metab Dispos 30:276-282.
Norinder U and Bergstroem CAS (2007) Prediction of ADMET properties. Chem Biol
3:1003-1042.
Obach RS, Baxter JG, Liston TE, Silber BM, Jones BC, MacIntyre F, Rance DJ and
Wastall P (1997) The prediction of human pharmacokinetic parameters from preclinical
and in vitro metabolism data. J Pharmacol Exp Ther 283:46-58.
Øie S and Tozer TN (1979) Effect of altered plasma protein binding on apparent volume
of distribution. J Pharm Sci 68:1203-1205.
27
DMD #20479
Riley RJ, McGinnity DF and Austin RP (2005) A unified model for predicting human
hepatic, metabolic clearance from in vitro intrinsic clearance data in hepatocytes and
microsomes. Drug Metab Dispos 33:1304-11.
Smith DA (1997) Physicochemical properties in drug metabolism and pharmacokinetics.
In Computer-Assisted Lead Finding and Optimisation (van de Waterbeemd H, Testa B,
Folkers G eds) pp 267-276, Wiley-VCH, Weinheim.

Tang H and Mayersohn M (2006) A global examination of allometric scaling for
predicting human drug clearance and the prediction of large vertical allometry. J Pharm
Sci 95:1783-1799.
van de Waterbeemd H, Smith DA and Jones BC (2001) Lipophilicity in PK design:
methyl, ethyl, futile. J Comp Aid Molec Design 15:273-286.
Veber DF, Johnson SR, Cheng H, Smith BR, Ward KW and Kopple KD (2002)
Molecular properties that influence the oral bioavailability of drug candidates. J Med
Chem 45:2615-2623.
Ward KW and Smith BR (2004a) A comprehensive quantitative and qualitative
evaluation of extrapolation of intravenous pharmacokinetic parameters from rat, dog, and
monkey to humans. I. Clearance. Drug Metab Dispos 32:603-611.
28
DMD #20479
Ward KW and Smith BR (2004b) A comprehensive quantitative and qualitative
evaluation of extrapolation of intravenous pharmacokinetic parameters from rat, dog, and
monkey to humans. II. Volume of distribution and mean residence time. Drug Metab
Dispos 32:612-619.
29
DMD #20479
Footnotes
Supporting Information Available: The complete list of compounds with pharmacokinetic
data, CAS numbers, full references and comments by the authors of this manuscript is
available as an Excel file. A color version of figures 2, 5, 9 and 10 is also available in a
Word file, as supporting information.
30
DMD #20479
FIGURE LEGENDS
FIGURE 1. Span of pharmacokinetic values for the 670 compounds included in this
analysis. Panel A: VDss; Panel B: CL; Panel C: t1/2; Panel D: fu.
FIGURE 2. Relationship between MRT and CL for acids (panel A), bases (panel B),
neutrals (panel C), and zwitterions (panel D). (Note: A color figure containing all of the
compounds in one plot is available in the Supplemental Information.)
FIGURE 3. Spans of physicochemical properties of the 670 compounds included in this
analysis. Panel A: molecular weight; Panel B: polar surface area; Panel C: charge; Panel

D: lipophilicity; Panel E: number of rotatable bonds per molecule; and Panel F: number
of hydrogen bond acceptors and donors per molecule.
FIGURE 4. Relationship between median human VDss values and selected
physicochemical parameters. Panel A: lipophilicity; Panel B: spans for human VDss
values by charge type (horizontal line corresponds to median value); Panel C: polar
surface area; and Panel D: sum of hydrogen bond acceptors and donors.
FIGURE 5. Relationship between VDss and lipophilicity, separated by charge type.
Panel A: VDss vs clogP for acids; Panel B: VDss vs clogP for bases; Panel C: VDss vs
clogP for neutrals; Panel D: VDss vs clogP for zwitterions; Panel E: free VDss vs clogP
for acids; Panel F: free VDss vs clogP for bases: Panel G: free VDss vs clogP for
neutrals; and Panel H: free VDss vs clogP for zwitterions. DHA-paclitaxel (clog P 15.7)
and eritoran (clogP 17.8) were excluded for easier visualization of the data. (Note: Color
figures containing all of the compounds in one plot is available in the Supplemental
Information.)
31
DMD #20479
FIGURE 6. Relationship between median human free VDss values and selected
physicochemical parameters. Panel A: lipophilicity; Panel B: charge; Panel C: polar
FIGURE 7. Relationship between median human CL values and selected
physicochemical parameters. Panel A: lipophilicity; Panel B: spans for human CL values
by charge type (horizontal line corresponds to median value); Panel C: polar surface area;
and Panel D: sum of hydrogen bond acceptors and donors.
FIGURE 8. Relationship between median human free CL values and selected

physicochemical parameters. Panel A: lipophilicity; Panel B: charge; Panel C: polar
FIGURE 9. Relationship between CL and lipophilicity, separated by charge type. Panel
A: CL vs clogP for acids; Panel B: CL vs clogP for bases; Panel C: CL vs clogP for
neutrals; Panel D: CL vs clogP for zwitterions; Panel E: free CL vs clogP for acids; Panel
F: free CL vs clogP for bases: Panel G: free CL vs clogP for neutrals; and Panel H: free
CL vs clogP for zwitterions. DHA-paclitaxel (clog P 15.7) and eritoran (clogP 17.8) were
excluded for easier visualization of the data. (Note: Color figures containing all of the
FIGURE 10. Relationship between protein binding and physicochemical properties.
Panel A: acids; Panel B: bases; Panel C: neutrals, Panel D: zwitterions; Lower Panel:
median free fraction vs lipophilicity. (Note: A color figure containing all of the
32
DMD #20479
TABLE 1. Summary of intravenous pharmacokinetic parameters and plasma protein
binding values for 670 compounds in humans.
Name VDss CL MRT t1/2
(L/kg) (mL/min/kg) fu (h) (h)
Abacavir 0.84 13 0.50 1.1 1.0
Abanoquil 6.3 14 NF 7.6 5.9
Acarbose 0.32 2.2 NF 2.4 2.7
Acebutolol 1.7 10 0.74 2.8 3.5
Acecainide (N-Acetylprocainamide) 1.9 4.0 0.90 7.9 6.4
Acetaminophen (Paracetamol) 1.0 5.0 0.52 3.3 2.5
Acetazolamide 0.37 0.65 0.04 9.5 13
N-Acetylcysteine 0.55 3.1 0.17 3.0 5.5
L-Acetylmethadol 8.3 5.4 0.20 26 18
Acetylsalicylic Acid 0.22 12 0.68 0.30 0.26

Acivicin 0.50 0.69 NF 12 9.9
Acyclovir 0.71 4.7 0.85 2.5 2.5
Adefovir 0.42 3.7 0.96 1.9 1.6
Adinazolam 0.98 6.2 0.31 2.6 2.1
Albuterol (Salbutamol) 1.9 7.8 0.92 4.1 2.4
Alcuronium 0.32 1.3 NF 4.1 3.6
Alfentanil 0.45 3.9 0.086 1.9 1.6
Alfuzosin 1.5 5.9 NF 4.2 4.8
Alizapride 1.6 6.6 NF 4.0 2.8
Allopurinol 0.58 11 0.97 0.88 0.80
Almotriptan 2.2 8.9 0.60 4.2 3.4
Alosetron 1.1 8.7 0.18 2.1 1.6
Alprazolam 0.80 0.74 0.29 18 12
Alprenolol 3.2 15 0.18 3.6 2.5
Amantadine 6.6 4.8 0.33 23 16
Amdinocillin 0.37 6.3 NF 1.0 1.1
Amikacin 0.16 1.1 0.88 2.4 2.4
9-Aminocamptothecin 2.2 6.5 0.003 5.6 7.0
6-Aminohexanoic Acid 0.39 2.5 0.92 2.6 4.9
5-Aminosalicylic Acid 0.33 9.3 0.39 0.59 0.61
Amiodarone 60 1.9 0.0002 620 820
Amitriptyline 8.7 6.1 0.07 24 17
Amlodipine 17 7.0 0.005 40 34
Amoxicillin 0.25 3.3 0.85 1.3 1.1
Amphetamine 6.1 9.7 0.80 10 7.3
Ampicillin 0.22 2.8 0.85 1.3 1.4
Amrinone 1.3 8.9 0.89 2.4 2.0
Amsacrine 1.6 4.3 0.029 6.2 4.7
Amsalog 0.30 2.6 0.0011 1.9 2.4
Anhydrovinblastine 12 12 NF 17 18
Anidulafungin 0.57 0.21 0.16 45 40
Antipyrine 0.77 0.64 0.93 20 12
33
DMD #20479
R-Apomorphine 1.6 40 0.06 0.67 0.68
Aprepitant 0.94 1.0 0.05 16 13
Argatroban 0.17 5.0 NF 0.57 0.40
Aripiprazole 4.9 0.83 0.01 98 75
Artesunate 15 1070 0.25 0.32 0.22
Atenolol 0.95 2.5 0.94 6.3 6.1
Atomoxetine 0.85 9.3 0.02 1.5 5.2
Atovaquone 0.60 0.15 0.001 67 63
Atracurium 0.10 5.7 0.52 0.29 0.31
Atropine 3.3 7.6 0.61 7.2 4.1
Azacitidine 0.47 35 NF 0.22 0.36
Azapropazone 0.12 0.14 0.004 14 17
Azelastine 15 9.0 0.17 27 22
Azimilide 13 2.4 0.06 100 79

Azithromycin 33 10 0.88 57 69
Azlocillin 0.26 2.5 0.65 1.7 1.2
Aztreonam 0.18 1.5 0.40 2.1 1.5
Bambuterol 1.6 18 NF 1.4 2.6
BB 83698 1.1 3.1 NF 5.9 9.4
Beclomethasone Dipropionate 0.29 36 0.13 0.10 0.50
Benperidol 3.8 8.3 NF 7.5 5.8
Betamethasone 1.3 2.8 0.36 7.9 5.6
Betamipron 0.28 9.2 0.17 0.51 0.59
Betaxolol 4.8 3.4 0.40 24 17
Bevantolol 0.67 5.5 0.015 2.0 1.9
Biapenem 0.20 2.5 0.92 1.3 1.1
Bilobalide 2.5 10 NF 4.0 3.2
Biperiden 12 12 0.097 17 24
Bisaramil 9.0 17 NF 8.8 8.6
Bisoprolol 2.4 3.7 0.66 11 10
BMS-214662 0.84 9.6 NF 1.4 1.6
Bortezomib 10 19 0.17 8.8 18
Bosentan 0.29 2.1 0.037 2.3 4.1
Bromazepam 0.85 0.51 0.48 28 21
Bromfenac 0.11 1.3 0.0011 1.5 2.6
Bromopride 3.1 13 0.60 4.0 2.9
Brotizolam 0.75 2.0 0.092 6.0 4.8
Budesonide 3.9 20 0.13 3.2 2.8
Buflomedil 1.3 5.6 0.40 3.9 3.3
Bufuralol 1.7 8.9 0.19 3.2 2.3
Bumetanide 0.16 2.5 0.031 1.1 1.2
Bunazosin 0.72 4.8 0.06 2.5 2.0
Bupivacaine 0.84 4.3 0.056 3.3 3.1
Buprenorphine 4.9 19 0.04 4.9 3.2
Busulphan 0.55 2.4 1.0 3.8 3.4
Butorphanol 12 41 0.17 5.3 4.8
34
DMD #20479
Caffeine 0.63 1.4 0.64 7.5 4.9
Captopril 0.75 12 0.73 1.0 2.0
Carbenicillin 0.17 1.9 0.52 1.5 1.1
Carboplatin 0.26 1.5 1.0 3.0 2.0
Carmustine (BCNU) 1.2 78 0.23 0.26 0.37
Carumonam 0.18 1.5 0.72 2.0 1.6
Carvedilol 1.3 7.8 0.02 2.8 2.4
Caspofungin 0.13 0.14 0.035 15 27
CB 10-277 0.25 1.3 NF 3.0 2.5
Cefadroxil 0.23 2.5 0.39 1.5 1.1
Cefamandole 0.16 3.6 0.25 0.75 0.75
Cefatrizine 0.22 3.3 0.40 1.1 1.2
Cefazolin 0.12 0.89 0.18 2.2 1.7
Cefcanel 0.13 2.6 NF 0.83 1.0

Cefepime 0.28 2.2 0.78 2.1 1.9
Cefetamet 0.28 1.9 0.78 2.5 2.1
Cefixime 0.24 1.0 0.31 3.9 3.2
Cefmetazole 0.13 1.5 0.15 1.5 1.5
Cefodizime 0.054 0.61 0.18 1.5 4.2
Cefoperazone 0.17 1.3 0.07 2.2 1.8
Ceforanide 0.17 0.66 0.19 4.3 3.0
Cefotaxime 0.19 2.7 0.60 1.2 1.2
Cefotetan 0.13 0.42 0.15 5.2 4.5
Cefoxitin 0.17 3.6 0.73 0.79 0.81
Cefpirome 0.24 1.9 0.90 2.1 1.7
Cefprozil 0.21 2.9 0.59 1.2 1.2
Ceftazidime 0.31 2.4 0.79 2.2 1.8
Ceftizoxime 0.20 2.1 0.72 1.6 1.5
Ceftobiprole 0.27 1.5 0.62 3.0 3.3
Ceftriaxone 0.085 0.26 0.052 5.4 8.6
Cefuroxime 0.15 2.2 0.12- 1.1 1.1
Cephalexin 0.21 3.9 0.60
0.85 0.89 0.57
Cephaloridine 0.46 3.3 0.80 2.3 1.5
Cephalothin 0.070 1.8 0.22 0.65 0.95
Cephapirin 0.13 2.7 0.55 0.80 1.2
Cephradine 0.21 3.3 0.95 1.1 0.85
Cerivastatin 0.33 2.9 0.01 1.8 1.8
Cetrorelix 0.39 1.2 0.14 5.4 12
Chlorambucil 0.26 2.8 0.01 1.5 1.1
Chloramphenicol 0.94 2.4 0.34 6.5 4.6
Chlorazepate 0.20 1.1 NF 3.0 2.4
Chlordiazepoxide 0.25 0.37 0.056 11 8.3
Chlormethiazole 6.6 33 0.36 3.3 4.5
m-Chlorophenylpiperazine 2.5 6.1 NF 7.0 4.7
Chloroquine 140 4.1 0.43 740 570
Chlorpheniramine 3.3 2.5 0.70 22 22
35
DMD #20479
Chlorpromazine 10 16 0.056 10 11
Chlorpropamide 0.19 0.045 0.03 70 46
Chlortetracycline 0.90 2.0 0.52 7.4 7.0
Chlorthalidone 3.9 1.5 0.24 43 36
Cibenzoline 4.1 8.6 0.50 7.8 7.3
Cicaprost 0.08 3.8 NF 0.35 1.1
Cidofovir 0.49 2.5 1.0 3.3 2.6
Cilastatin 0.15 2.3 0.60 1.1 0.86
Cilomilast 0.23 0.50 0.006 8.5 7.9
Cimetidine 1.2 8.1 0.78 2.5 2.2
Ciprofloxacin 2.1 8.3 0.70 4.2 3.8
Cisatracurium 0.14 5.4 0.62 0.43 0.42
Citalopram 12 4.3 0.20 47 33
Cladribine 7.7 14 0.79 9.2 16

Clarithromycin 1.5 7.3 0.23 3.4 2.8
Clavulanic Acid 0.22 3.1 0.91 1.0 0.90
Clevidipine 0.58 142 0.0038 0.07 0.30
Clinafloxacin 1.9 4.7 0.96 6.7 5.4
Clindamycin 0.79 4.5 0.06 2.9 2.1
Clomipramine 13 8.2 0.029 26 26
Clonazepam 2.9 0.88 0.15 55 38
Clonidine 3.3 4.0 0.56 14 7.6
Clozapine 1.6 2.5 0.055 11 10
Cocaethylene 1.6 13 0.64 2.0 1.5
Cocaine 2.0 32 0.12 1.0 0.76
Codeine 3.5 15 0.70 3.9 4.0
Colchicine 6.1 2.1 0.61 49 58
Conivaptan 0.76 3.0 0.01 4.2 6.7
Cotinine 1.1 0.89 NF 21 17
Cyclophosphamide 0.73 1.1 0.87 11 8.0
Cyclosporine 3.3 7.5 0.068 7.3 7.3
Dacarbazine 1.2 2.6 1.0 7.8 6.2
Dalbavancin 0.14 0.010 0.02 230 170
Dalfopristin 0.39 16 0.82 0.41 0.74
Dantrolene 0.37 0.43 NF 14 10
Dapsone 0.83 0.48 0.25 29 22
Daptomycin 0.088 0.16 0.083 9.2 8.1
Darifenacin 2.6 12 0.02 3.6 3.6
Decitabine 4.6 130 1.0 0.59 0.58
Delorazepam 2.2 0.17 0.051 220 200
(Chlordesmethyldiazepam)
Demethylchlortetracycline 1.3 1.1 0.59 17 12
Denaverine 7.1 5.7 NF 21 34
4-Desacetyl-4-Methylpaclitaxel 6.9 8.6 NF 13 31
carbonate
Desipramine 15 11 0.16 23 22
Desmethyldiazepam 0.45 0.12 0.03 63 46
Desmopressin 0.30 1.4 NF 3.6 3.0
36
DMD #20479
Dexamethasone 0.94 3.3 0.32 4.7 3.7
Dexfenfluramine 11 11 0.66 18 14
Dexloxiglumide 0.18 3.7 0.024 0.79 1.2
Dexmedetomidine 1.6 11 0.06 2.5 2.2
Dexniguldipine 8.4 9.3 NF 15 22
Dexrazoxane 0.55 3.1 1.0 3.0 2.5
DHA Paclitaxel 0.068 0.025 0.0038 45 60
Diatrizoic Acid (Amidotrizoate) 0.26 1.7 1.0 2.6 1.8
Diazepam 1.0 0.38 0.023 44 42
Diazoxide 0.21 0.060 0.06 58 48
Dibekacin 0.13 0.80 NF 2.7 2.4
Dichloroacetic Acid 0.19 5.3 NF 0.60 0.65
Diclofenac 0.22 3.5 0.005 1.0 1.4
Dicloxacillin 0.11 2.0 0.033 0.92 0.88

Didanosine 0.77 11 0.95 1.2 1.4
Diflunisal 0.097 0.10 0.0016 14 10
Digitoxin 0.44 0.043 0.066 170 180
Digoxin 4.1 1.7 0.70 40 38
Dihydroquinidine 2.8 4.2 0.22 11 5.7
Dilevalol 4.8 29 NF 2.8 3.3
Diltiazem 4.1 13 0.18 5.3 5.6
Diphenhydramine 6.5 9.8 0.19 11 9.3
Diprafenone 1.2 11 0.017 1.9 1.5
Diprophylline 0.42 4.8 NF 1.5 1.7
Disopyramide 0.52 0.90 0.16 9.6 7.0
Docetaxel 2.1 14 0.04 2.5 11
Dofetilide 3.3 5.2 0.36 11 8.1
Dolasetron 2.0 180 NF 0.19 0.13
Domperidone 3.4 9.5 0.082 6.0 7.5
Doxacurium 0.22 2.7 0.53 1.4 1.7
Doxapram 1.2 5.3 NF 3.7 4.1
Doxazosin 1.3 1.6 0.017 14 10
Doxepin 12 14 0.20 15 15
Doxifluridine 0.28 11 0.61 0.46 0.35
Doxorubicin 22 15 0.28 24 32
Doxycycline 0.69 0.46 0.12 25 14
DP-b 99 1.1 14 NF 1.3 3.5
Drotaverine 1.9 3.5 0.12 9.0 9.3
Edrophonium 1.1 9.6 NF 1.9 1.8
Eletriptan 1.6 5.3 0.15 5.0 4.2
Eltanolone 2.0 22 0.010 1.5 4.7
Enalaprilat 0.38 1.6 0.62 4.0 39
Encainide 2.2 13 0.26 2.8 2.6
Endralazine 2.2 13 NF 2.7 5.6
Eniporide 1.1 8.2 NF 2.3 2.2
Enoxacin 2.0 5.4 0.80 6.2 5.1
37
DMD #20479
Enprofylline 0.63 4.0 0.55 2.6 1.8
Entacapone 0.27 12 0.02 0.38 2.4
Epirubicin 45 20 0.25 38 36
Epristeride 0.54 0.33 0.03 27 27
Eprosartan 0.17 1.9 0.017 1.5 2.1
Eptifibatide 0.17 1.2 0.75 2.4 4.2
Ergotamine 3.6 15 0.02 4.0 2.1
Eritoran 0.048 0.013 NF 62 51
Ertapenem 0.12 0.45 0.10 4.4 3.8
Erythromycin 0.95 5.6 0.10 2.8 2.0
Esmolol 1.2 290 0.59 0.070 0.15
Estradiol 1.2 30 0.016 0.7 1.7
Estramustine Phosphate 0.12 0.94 NF 2.1 2.4
Ethacrynic Acid 0.26 8.7 NF 0.50 0.50

Ethambutol 1.7 10 0.18 2.7 3.1
Ethinylestradiol 4.3 7.0 0.014 11 9.7
Ethinylestradiol-17-Sulfate 0.61 1.3 NF 7.8 9.3
Ethinylestradiol-3-Sulfate 2.3 4.7 0.011 8.2 8.4
Etilefrine 2.1 14 0.77 2.5 2.2
Etomidate 2.7 13 0.23 2.9 3.5
Etoposide 0.18 0.50 0.12 6.0 5.7
Etoricoxib 1.5 0.79 0.081 32 26
Exatecan (Acid) 0.44 0.96 NF 7.6 6.7
Famotidine 1.2 6.6 0.84 3.0 2.8
Felodipine 4.4 11 0.0036 6.7 10
Fenoterol 1.2 29 0.53 0.69 0.87
Fenoximone 1.8 29 0.30 1.0 1.0
Fenspiride 3.0 2.6 NF 19 14
Fentanyl 0.89 4.7 0.16 3.2 3.0
Finasteride 1.1 2.4 0.095 7.6 6.0
Flavopiridol 1.5 6.1 0.06 4.0 5.2
Flecainide 6.1 4.9 0.52 21 12
Fleroxacin 1.6 2.4 0.73 11 8.6
Flucloxacillin 0.19 2.4 0.043 1.3 1.4
Fluconazole 0.75 0.31 0.89 40 30
Flucytosine 0.68 2.0 1.0 5.7 4.2
Fludarabine 2.2 3.2 0.76 12 11
Flumazenil 0.80 16 0.58 1.0 0.78
Flunitrazepam 1.9 1.4 0.17 23 25
Fluorescein 0.14 1.3 0.11 1.8 1.6
5-Fluorouracil 0.23 26 0.64 0.15 0.12
Flupirtine 1.1 1.6 0.15 11 8.5
Fluticasone Propionate 3.6 17 0.10 3.9 6.0
Fluvastatin 0.42 16 0.0079 0.44 0.70
Folinic Acid 0.25 5.8 0.087 0.80 1.3
Foscarnet 0.50 2.1 0.85 4.0 4.7
38
DMD #20479
Fosfluconazole 0.15 1.3 0.042 2.0 2.1
Fosfomycin 0.32 2.0 1.0 2.7 1.9
Fosinoprilat 0.13 0.32 0.006 6.8 9.4
Fostriecin 0.086 1.2 NF 1.2 1.5
Frovatriptan 3.6 2.5 0.85 22 24
Furosemide 0.12 1.6 0.012 1.3 2.5
Gabapentin 0.71 1.7 0.97 7.0 5.3
Gadoversetamide 0.16 1.2 1.0 2.2 1.7
Galanthamine 2.3 5.6 0.83 6.8 5.3
Ganciclovir 1.0 4.6 0.99 3.7 3.7
Gatifloxacin 1.7 2.8 0.80 11 10
Gefitinib 23 12 0.089 32 34
Gemcitabine 1.5 32 1.0 0.81 1.0
Genaconazole 0.62 0.19 NF 54 49

Gentamicin 0.33 1.0 1.0 5.5 4.7
Gestodene 0.46 0.80 0.023 9.6 10
Ginkgolide A 0.62 2.3 NF 4.6 3.8
Ginkgolide B 0.91 2.3 NF 6.6 5.2
Glimepiride 0.19 0.50 0.005 6.3 10
Glipizide 0.16 0.56 0.02 4.8 3.3
Glyburide 0.080 0.82 0.021 1.6 2.2
Granisetron 3.7 9.1 0.35 6.7 5.2
Guanfacine 5.6 4.5 0.28 22 15
Haloperidol 17 7.8 0.08 36 35
Hexobarbital 1.1 3.4 0.53 5.4 4.9
Hydralazine 1.5 85 0.12 0.29 1.0
Hydrocortisone 0.38 5.7 0.20 1.9 1.6
Hydroflumethazide 2.2 9.7 NF 3.8 5.2
Hydromorphone 4.3 28 0.86 2.6 2.3
Hydroxychloroquine 700 11 0.57 1300 850
3’-Hydroxycotinine 0.85 1.8 NF 7.9 5.9
3(S)-Hydroxydihydroquinidine 6.8 12 0.47 9.4 6.7
2-Hydroxyimipramine 6.6 9.2 0.36 12 10
7-Hydroxystaurosporine 0.15 0.0037 0.0022 680 790
Hydroxyurea 0.52 1.5 1.0 4.8 3.4
Hypericin 0.25 0.13 NF 32 42
Ibandronic Acid (Ibandronate) 0.55 1.8 0.15 5.1 14
Ibuprofen 0.15 0.82 0.006 3.0 1.6
Ibutilide 12 26 0.60 7.7 7.0
Idarubicin 38 24 0.076 26 16
Idazoxan 3.3 10 NF 5.5 4.2
Ifetroban 4.4 6.4 NF 11 22
Ifosfamide 0.62 1.1 1.0 9.4 6.6
Iloprost 0.37 16 0.40 0.39 0.57
Imatinib 3.9 3.3 0.05 20 22
Imipenem 0.24 3.0 0.86 1.3 0.95
39
DMD #20479
Imipramine 12 13 0.075 15 16
Imipramine N-oxide 1.9 12 NF 2.6 1.8
Indinavir 0.82 18 0.36 0.76 1.0
Indocyanine Green 0.035 6.8 0.05 0.086 0.065
Indomethacin 0.096 1.3 0.01 1.2 1.4
Indoramin 4.9 20 0.15 4.1 4.3
Intoplicine 11 18 NF 11 19
Iohexol 0.16 2.0 1.0 1.3 1.5
Iopamidol 0.28 1.9 1.0 2.5 2.1
Iopromide 0.22 1.4 0.99 2.6 2.6
Iothalamic Acid (Iothalamate) 0.17 2.4 0.98 1.2 1.3
Irbesartan 0.94 2.3 0.10 6.8 14
Irinotecan 3.5 7.0 0.51 8.3 9.0
Irofulven 3.1 140 NF 0.40 0.30

Isepamicin 0.32 1.3 0.95 4.1 24
Isoniazide 0.82 7.4 1.0 1.8 1.0
Isoproterenol 1.5 56 0.71 0.43 0.41
Isosorbide Dinitrate 1.9 31 0.72 1.0 1.7
Isosorbide-2-Mononitrate 0.86 6.2 NF 2.3 1.9
Isosorbide-5-Mononitrate 0.70 2.0 1.0 5.8 4.1
Isoxicam 0.19 0.07 0.035 44 33
Isradipine 1.5 26 0.04 1.0 3.3
Itraconazole 7.4 5.1 0.002 24 25
IVL745 0.25 11 NF 0.38 1.6
Ixabepilone 11 10 NF 18 17
Kanamycin 0.26 1.4 0.99 3.1 2.1
Ketamine 2.9 19 0.47 2.5 2.8
Ketanserin 3.9 6.7 0.055 9.7 12
Ketobemidone 0.48 9.2 NF 0.87 2.3
Ketoprofen 0.13 1.6 0.008 1.4 2.1
Ketorolac 0.11 0.35 0.0068 5.2 5.1
KRN-5500 0.17 2.7 NF 1.1 1.3
KW-2170 12 18 NF 11 32
Labetalol 4.8 23 0.50 3.5 4.4
Lamifiban 0.29 1.9 0.94 2.5 2.1
Lamivudine 1.3 4.8 0.94 4.4 9.1
Lansoprazole 0.28 4.4 0.021 1.1 1.0
Letrozole 1.9 0.57 0.41 59 45
Leuprolide 0.38 2.0 0.54 3.1 2.9
Levodopa 1.7 23 0.76 1.2 1.3
Levofloxacin 1.2 1.9 0.75 11 8.8
Levomepromazine 12 9.9 NF 21 30
Levonorgestrel 1.5 1.8 0.025 14 9.4
Levosimendan 0.24 3.8 0.02 1.1 1.1
Lidocaine 1.8 16 0.33 1.9 1.6
Lincomycin 1.0 2.1 0.14- 7.5 5.6
0.72
40
DMD #20479
Linezolid 0.58 1.8 0.69 5.4 4.5
Lisinopril 0.89 1.2 1.0 12 42
Lithium Carbonate 0.62 1.3 1.0 7.9 7.8
Lorazepam 1.3 1.0 0.09 22 17
Lorcainide 6.6 16 0.15 6.9 6.5
Lormetazepam 1.6 4.0 0.12 6.7 4.9
Losartan 0.37 8.2 0.01 0.75 1.8
Lovastatin (acid) 0.87 7.2 0.043 1.3 1.4
Loxiglumide 0.24 1.0 NF 4.0 5.2
Maprotiline 45 14 0.11 54 51
Maxipost 10 15 0.0038 11 37
Mebendazole 1.2 15 0.086 1.3 1.1
Medroxalol 7.9 16 NF 8.2 11
Melagatran 0.23 1.9 0.93 2.0 1.6

Meloxicam 0.15 0.12 0.003 21 18
Melperone 14 46 NF 5.0 3.9
Melphalan 0.48 7.0 0.14 1.1 1.0
MEN-10755 2.4 2.5 NF 17 21
Meperidine 2.3 4.9 0.42 6.4 7.9
Mepivacaine 0.95 6.8 0.30 2.5 2.0
Meprobamate 0.70 0.60 1.0 19 14
Meptazinol 3.3 28 0.73 2.0 1.7
6-Mercaptopurine 1.0 15 0.85 1.1 1.0
Meropenem 0.30 3.9 0.87 1.3 1.0
Metformin 0.64 7.4 1.0 1.4 1.7
Methadone 4.4 1.7 0.21 43 31
Methamphetamine 4.3 4.4 0.85 16 12
Methicillin 0.32 6.6 0.43 0.80 0.64
Methimazole 0.86 3.7 NF 3.8 2.4
Methohexital 1.1 12 0.27 1.5 1.6
Methotrexate 0.43 2.1 0.37 3.4 3.9
Methyldopa 0.69 3.5 0.85 3.3 5.9
Methylnaltrexone 2.6 22 NF 2.0 2.5
7α-Methyl-19-Nortestosterone 0.80 20 NF 0.67 0.65
Methylphenidate 2.2 0.55 0.85 4.5 4.8
Methylprednisolone 1.2 6.1 0.23 3.5 2.3
7-Methylthiomethylpaclitaxel 11 6.4 NF 29 32
Metoclopramide 3.2 5.7 0.60 9.4 7.2
Metocurine 0.40 1.2 0.65 5.6 5.1
Metolazone 1.6 1.4 0.05 19 20
Metoprolol 3.1 13 0.88 4.0 3.6
Metrizoate 0.17 2.7 1.0 1.0 1.3
Metronidazole 0.40 0.85 0.96 7.8 7.1
Mexiletine 5.9 8.3 0.36 12 9.9
Mezlocillin 0.09 2.1 0.70 0.71 1.2
Mibefradil 3.1 4.0 0.005 13 13
41
DMD #20479
Micafungin 0.21 0.17 0.0023 21 16
Midazolam 1.1 5.3 0.017 3.5 3.1
Miglitol 0.28 1.7 1.0 2.7 2.3
Milrinone 0.25 6.2 0.035 0.67 0.80
Minocycline 1.6 1.2 NF 22 17
Mirtazapine 4.2 8.0 0.15 8.8 15
Mitoxantrone 12 7.9 0.25 25 53
Mivacurium (cis/cis) 0.27 5.2 0.70 0.87 0.83
Moclobemide 1.1 10 0.77 1.8 1.5
Montelukast 0.15 0.68 0.002 3.8 5.0
Morphine 2.3 26 0.65 1.5 2.0
Morphine-6-Glucuronide 0.12 2.2 NF 0.91 1.4
Moxalactam 0.17 0.72 0.39 3.9 2.9
Moxifloxacin 1.4 2.4 0.60 9.7 8.2

Moxonidine 1.8 11 0.93 2.7 2.2
Nadolol 1.9 2.9 0.14 11 9.2
Nafcillin 0.22 3.3 0.13 1.1 0.70
Nalbuphine 4.6 22 0.50 3.5 3.7
Nalmefene 8.2 15 0.65 9.1 8.8
Naloxone 1.7 23 0.54 1.2 1.1
Naltrexone 7.6 57 0.79 2.2 1.9
Napsagatran 0.36 6.4 NF 0.94 1.9
Naratriptan 2.4 6.6 0.70 6.1 6.6
Nateglinide 0.15 1.8 0.029 1.4 1.5
Nebivolol 11 14 NF 13 10
Nefazodone 0.51 7.5 0.01 1.1 1.2
Nefopam 5.6 12 NF 8.1 5.0
Nelarabine 4.9 81 0.80 1.0 0.50
Neostigmine 0.74 9.2 NF 1.3 1.3
Netilmicin 0.073 0.55 1.0 2.2 3.2
Nevirapine 1.3 0.30 0.32 81 53
Nicardipine 1.0 11 0.01 1.5 4.1
Nicotine 2.6 18 0.95 2.4 2.0
Nifedipine 0.79 7.3 0.044 1.8 1.9
Nimodipine 1.1 15 0.016 1.2 1.3
Nisoldipine 5.5 15 0.003 6.5 11
Nitrazepam 1.7 0.86 0.13 33 26
Nitrendipine 6.1 25 0.02 4.1 8.2
Nitrofurantoin 0.57 9.7 0.17 0.98 0.97
Nizatidine 1.0 9.8 0.65 1.7 1.5
NK 611 0.30 0.40 0.013 17 14
Nomifensine 6.0 22 0.40 4.5 6.5
Nortilidine 2.5 9.9 NF 4.2 4.4
Nortriptyline 22 10 0.12 37 30
Ofloxacin 1.6 2.5 0.75 11 8.9
Olcegepant 0.31 2.6 NF 1.9 2.5
42
DMD #20479
Olsalazine 0.070 1.2 NF 0.97 0.90
Omeprazole 0.24 8.4 0.05 0.48 0.58
Ondansetron 1.8 5.8 0.27 5.2 3.4
Oseltamivir Acid 0.37 4.8 0.97 1.3 1.8
Oxacillin 0.19 6.3 0.07 0.50 0.70
Oxazepam 0.59 1.1 0.04 8.9 6.7
Oxiracetam 0.55 1.8 NF 4.9 7.5
Oxybutynin 0.85 5.1 0.0034 2.7 7.2
Oxycodone 2.5 6.1 0.55 6.8 5.5
Oxytetracycline 1.7 2.0 0.90 12 10
Paclitaxel 3.0 6.4 0.12 7.8 11
Palonosetron 6.3 2.6 0.38 40 39
Pamidronic Acid (Pamidronate) 1.8 2.5 NF 12 32
Pancuronium 0.20 1.5 0.090 2.2 1.9

Panipenem 0.19 2.6 NF 1.2 0.96
Pantoprazole 0.17 2.2 0.02 1.9 1.9
Papaverine 1.0 11 0.073 1.4 1.8
Paricalcitol 0.41 0.89 0.0016 7.7 5.3
Paroxetine 18 18 0.06 17 13
Pefloxacin 1.5 2.0 0.75 13 11
Penciclovir 1.1 8.4 0.84 2.4 2.1
Penicillin G 0.24 6.9 0.40 0.58 0.70
Pentamidine 53 74 NF 12 25
Pentazocine 3.4 23 0.39 2.5 2.5
Pentobarbital 0.91 0.47 0.39 32 22
Pentoxifylline 1.8 39 NF 0.77 1.2
Perindoprilat 0.76 1.7 0.16 7.6 29
Perphenazine 18 27 0.07 11 9.4
Phenacetin 1.4 21 0.47 1.1 0.92
Phencyclidine 6.9 5.1 0.35 23 16
Phenethicillin 0.30 4.2 0.25 1.2 0.91
Phenobarbital 0.54 0.063 0.49 140 99
Phenoxymethylpenicillin 0.41 6.8 0.45 1.0 0.84
Pimobendan 2.0 14 0.024 2.2 1.8
Pindolol 1.2 7.7 0.58 2.6 2.2
Piperacillin 0.27 4.0 0.50 1.1 0.96
Pipercuronium 0.35 3.0 0.98 1.9 1.9
Piretanide 0.17 3.1 0.058 0.91 1.3
Piritramide 4.7 7.8 0.061 10 8.0
Pirmenol 1.4 1.8 0.13 13 8.4
PNU-145156E 0.27 0.0047 NF 960 730
Pravastatin (acid) 0.46 14 0.50 0.59 0.78
Prazosin 0.73 4.7 0.060 2.6 2.0
Prednisolone 0.86 2.9 0.25 4.8 3.4
Prednisone 0.57 2.5 0.27 3.8 2.9
Prilocaine 3.7 29 0.72 2.2 1.8
43
DMD #20479
Primaquine 4.0 5.8 NF 11 7.1
Probenecid 0.13 0.25 0.13 8.7 5.9
Procainamide 2.2 10 0.84 3.7 3.1
Prochlorperazine 22 16 NF 23 9.0
Procyclidine 0.74 0.86 NF 14 12
Promazine 8.1 14 0.11 9.6 7.9
Promethazine 14 14 0.09 17 14
Propafenone 2.2 16 0.038 2.2 2.1
Propofol 4.7 36 0.016 2.2 3.2
Propoxyphene 12 15 0.24 13 18
Propranolol 3.1 12 0.13 4.3 3.4
Propylthiouracil 0.34 3.1 0.18 1.8 1.3
Pseudohypericin 0.56 0.62 NF 15 20
Pyridostigmine 1.1 9.6 1.0 1.8 1.5

Pyrimethamine 0.43 0.052 0.095 140 140
Quercetin 0.12 11 0.009 0.20 0.60
Quinacrine 45 5.1 0.13 150 120
Quinaprilat 0.13 0.93 0.32 2.3 2.3
Quinidine 2.9 4.0 0.26 12 6.6
Quinine 1.8 1.9 0.30 16 11
Quinupristin 0.67 16 0.34 0.70 0.87
Rabeprazole 0.22 4.0 0.037 0.92 1.0
Ranitidine 1.2 9.6 0.95 2.1 2.1
Reboxetine 0.65 0.82 0.019 13 10
Recainam 1.4 4.5 0.86 5.2 5.0
Remifentanil 0.40 37 0.30 0.18 0.80
Remoxipride 0.65 1.7 0.16 6.4 5.5
Repaglinide 0.35 7.8 0.015 0.75 0.87
Repinotan 0.21 2.2 NF 1.6 1.2
Ribavirin 14 5.2 1.0 45 45
Ribostamycin 0.25 1.5 NF 2.8 2.5
Rifabutin 9.3 2.4 0.29 65 37
Rifampin 0.97 3.5 0.20 4.6 3.8
Risedronic Acid (Risedronate) 6.3 1.5 0.76 70 200
Risperidone 1.1 5.4 0.10 3.4 3.2
Ritodrine 4.4 31 0.64 2.4 2.6
Rivastigmine 1.3 12 0.60 1.9 1.4
Rizatriptan 1.9 16 0.86 2.0 2.2
Rocuronium 0.21 3.7 0.54 0.95 1.6
Rolitetracycline 0.54 0.97 0.50 9.3 8.8
Romidepsin 1.2 7.4 NF 2.6 11
Ropivacaine 0.75 5.5 0.06 2.3 2.2
Roquinimex 0.21 0.082 NF 43 31
Rosiglitazone 0.20 0.65 0.002 5.1 3.9
Rosuvastatin 1.7 11 0.12 2.6 2.0
RPR 109881A 12 14 NF 14 20
44
DMD #20479
Saquinavir 3.6 13 0.028 4.6 13
SarCNU 0.76 9.0 NF 1.4 1.0
Sch34343 0.30 7.5 0.35 0.67 0.80
Scopolamine 3.1 16 NF 3.2 4.5
Selegiline 1.9 20 0.13 1.6 1.3
Sematilide 0.82 3.7 0.96 3.7 3.8
Sildenafil 1.4 9.1 0.04 2.6 3.9
Sisomicin 0.19 1.0 0.15 3.2 2.4
Sitafloxacin 1.5 3.7 0.51 6.7 6.6
Sitagliptin 2.8 6.0 0.62 7.8 12
Solifenacin 8.2 2.1 0.02 65 52
Sotalol 1.3 2.0 0.62 11 6.3
Sparfloxacin 3.9 2.7 0.55 24 20
Spectinomycin 0.13 0.99 NF 2.2 1.8

Squalamine 0.23 1.2 NF 3.2 9.5
Stavudine 0.67 8.2 1.0 1.4 1.4
Streptomycin 0.34 0.78 0.65 7.3 4.3
Sufentanil 9.4 15 0.075 10 14
Sulbactam 0.32 5.1 0.62 1.0 1.1
Sulbenicillin 0.15 1.6 0.50 1.6 1.2
Sulfadiazine 0.29 0.55 0.44 8.8 7.0
Sulfamethoxazole 0.30 0.36 0.23 14 9.8
Sulfinpyrazone 0.12 0.34 0.017 5.9 6.2
Sulfisoxazole 0.17 0.30 0.079 9.4 7.4
Sumatriptan 1.7 19 0.83 1.5 1.7
Suprofen 0.040 0.76 0.006 0.88 2.1
Suramin 0.54 0.0057 0.003 1400 1200
Tacrine 11 56 0.25 3.3 3.3
Tacrolimus 1.2 0.70 0.01 27 26
Talinolol 3.3 4.9 0.39 11 11
Tamsulosin 0.21 0.62 0.01 5.6 6.8
Tegaserod 5.3 18 0.02 4.9 11
Teicoplanin A2-1 1.5 0.20 0.11 140 150
Telavancin 0.11 0.20 0.07 9.2 6.7
Telithromycin 3.0 14 0.41 3.6 12
Telmisartan 5.3 8.4 0.004 11 20
Temozolomide 0.50 3.6 NF 2.3 1.5
Temsirolimus 3.0 7.7 NF 10 18
Teniposide 0.41 0.19 0.0044 37 16
Tenofovir 0.83 3.1 0.93 3.8 5.8
Tenoxicam 0.19 0.03 0.0085 92 67
Terazosin 0.98 1.1 0.08 15 9.0
Terbutaline 1.5 3.4 0.75 7.4 15
Terodiline 5.1 1.1 0.08 81 56
Tesaglitazar 0.13 0.039 0.0011 56 45
Tetracycline 1.2 1.5 0.78 12 9.4
45
DMD #20479
∆9-Tetrahydrocannabinol 8.9 3.2 0.05 46 33
Tezosentan 0.28 8.1 0.0085 0.58 3.8
Thalidomide 0.95 3.4 0.40 4.3 4.7
Theophylline 0.51 0.86 0.61 9.9 7.2
Thionylan (Methapyrilene) 3.3 28 NF 2.0 1.6
Thiopental 1.2 8.2 0.14 2.4 2.0
Thiotepa 1.6 6.7 0.90 4.0 2.7
Tiagabine 1.1 1.6 0.04 12 10
Tiazofurin 1.1 2.4 NF 7.6 5.9
Ticarcillin 0.16 1.8 0.55 1.5 1.0
Tigecycline 12 3.8 0.20 53 48
Tilidine 4.0 16 0.21 4.2 5.0
Timolol 1.5 8.5 0.90 3.0 2.2
Tinidazole 0.59 0.60 0.80 16 13

Tirapazamine 0.56 8.9 0.81 1.0 0.78
Tirofiban 0.99 4.3 0.36 1.8 1.6
Tizanidine 2.4 11 0.70 3.6 2.4
Tobramycin 0.23 1.6 1.0 2.4 2.0
Tocainide 1.8 2.2 0.87 14 12
Tolamolol 4.0 14 0.089 4.8 2.5
Tolbutamide 0.12 0.21 0.05 9.5 7.0
Tolcapone 0.12 1.9 0.0012 1.1 1.1
Toloxatone 1.5 11 0.49 2.3 1.6
Tolterodine 1.5 8.4 0.037 3.0 2.4
Tomopenem 0.23 1.9 0.91 2.0 1.7
Topixantrone 57 27 NF 39 45
Topotecan 1.8 13 0.65 2.3 2.3
Torsemide 0.21 0.53 0.01 6.6 5.1
Trabectedin 25 12 NF 35 44
Tramadol 2.8 6.5 0.80 7.2 5.8
Tranexamic Acid 0.38 2.4 NF 2.6 2.3
Traxoprodil 4.4 27 0.63 2.6 3.7
Trazodone 0.52 1.4 NF 6.2 7.3
Triamcinolone Acetonide 1.4 9.4 0.20 2.5 2.4
Triamterene 13 63 0.42 3.4 4.3
Triazolam 0.58 3.0 0.10 3.2 2.7
Trimazosin 0.18 0.96 NF 3.1 3.1
Trimethoprim 1.5 2.1 0.50 12 9.6
Trimetrexate 0.77 0.77 0.05 17 17
Trimipramine 16 16 0.051 17 23
Tropisetron 9.7 26 NF 6.3 5.6
Trospectomycin 0.70 1.7 NF 6.9 11
Trovafloxacin 1.3 1.4 0.24 15 11
Troxacitabine 1.0 2.4 NF 6.9 82
Tubocurarine 0.45 3.4 0.58 2.2 2.0
UK-240,455 0.80 6.0 0.13 2.2 1.4
46
DMD #20479
Urapidil 0.75 3.1 NF 4.0 3.5
Valproic Acd 0.14 0.16 0.08 15 12
Valsartan 0.22 0.49 0.04 7.5 9.5
Valspodar 1.8 2.6 0.022 12 10
Vancomycin 0.54 1.3 0.70 6.9 6.5
Vardenafil 3.0 13 0.05 3.8 4.5
Vecuronium Bromide 0.30 4.5 0.25 1.1 1.4
Venlafaxine 4.4 14 0.73 5.2 5.0
Verapamil 3.7 18 0.093 3.4 2.8
Verlukast 0.11 0.68 0.0004 2.7 2.3
Viloxazine 0.73 2.1 NF 5.8 4.1
Vinblastine 28 3.1 0.14 150 67
Vincristine 2.4 2.0 0.40 20 23
Vindesine 5.0 2.2 NF 38 35

Vinorelbine 23 20 0.87 18 26
Voriconazole 2.2 8.3 0.42 4.4 5.6
Vorinostat 0.50 28 0.29 0.30 0.76
Warfarin 0.13 0.055 0.015 39 29
Xamoterol 0.64 3.0 0.97 3.6 7.7
Zalcitabine 0.54 5.6 NF 1.6 1.2
Zaleplon 1.3 16 0.40 1.4 1.1
Zanamivir 0.23 1.6 0.86 2.4 1.7
Zidovudine 1.8 25 0.80 1.2 1.3
Ziprasidone 1.0 5.1 0.0012 3.3 3.1
Zoledronic Acid 0.60 2.2 0.78 4.5 11
Zolmitriptan 1.8 6.7 0.75 4.6 3.6
Zolpidem 0.54 4.3 0.08 2.1 1.7
Zonampanel 0.19 5.3 NF 0.60 0.78
Zopiclone 1.3 3.3 0.20 6.6 5.2
Zotarolimus 1.3 0.67 NF 33 35
NF, data not found
47
DMD #20479
TABLE 2. Characteristics of the human intravenous pharmacokinetic parameters and
plasma protein binding for 670 compounds.
Parameter N %
Steady-State Volume of Distribution (VDss)

compounds less than 0.1 L/kg 17 2.5
compounds between 0.1 and 0.7 L/kg 260 39
compounds between 0.7 and 2 L/kg 197 29
compounds between 2 and 10 L/kg 143 21
compounds 10 L/kg or greater 53 7.9
Clearance (CL)

compounds less than 1 mL/min/kg 104 16
compounds between 1 and 5 mL/min/kg 262 39
compounds between 5 and 15 mL/min/kg 200 30
compounds between 15 and 21 mL/min/kg 48 7.2
compounds greater than 21 mL/min/kg 56 8.4
Half-Life (t½)
compounds less than 1 hr 64 10
compounds between 1 and 4 hr 266 40
compounds greater than 24 hr 82 12
Plasma Protein Binding

compounds greater than 99.9% bound 41 7.4
compounds between 99 and 99.9% bound 28 5.1
compounds between 90 and 99% bound 116 21
compounds between 50 and 90% bound 167 30
compounds less than 50% bound 202 36
48
DMD #20479
TABLE 3. Comparison of median values for total and free VDss and CL values relative
to charge type.
median median median median

Charge Type (N) VDss free VDss CL free CL
Acids (159) 0.22 2.2 2.1 17

Bases(267) 2.3 9.2 7.6 23
Neutrals (173) 1.1 5.5 4.0 21
Zwitterions (68) 0.83 2.0 2.4 3.8
Gatoversetamide, gentamycin and lithium carbonate are not included in the charge classes.
49
DMD Fast Forward. Published on April 21, 2008 as DOI: 1
This article has not been copyedited and formatted. The final versio
md.aspetjournals.org at ASPET Journals on May 10, 2016
DMD Fast Forward. Published on April 21, 2008 as DOI: 10.1124/dmd.1
This article has not been copyedited and formatted. The final version may differ
nloaded from dmd.aspetjournals.org at ASPET Journals on May 10, 2016
This article has not been copyedited and formatted. The final version may differ from this versio

Trend Analysis of A Database of Intravenous Pharmacokinetic Parameters in Humans For 670 Drug Compounds

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Trend Analysis of A Database of Intravenous Pharmacokinetic Parameters in Humans For 670 Drug Compounds

Uploaded by

Copyright:

Available Formats

DMD Fast Forward. Published on April 21, 2008 as DOI: 10.1124/dmd.108.

TREND ANALYSIS OF A DATABASE OF INTRAVENOUS

R. Scott Obach†, Franco Lombardo,*§ Nigel J. Waters#

Pharmacokinetics Dynamics and Metabolism, Pfizer Global Research and Development,

Downloaded from dmd.aspetjournals.org at ASPET Journals on May 10, 2016

TREND ANALYSIS OF PHARMACOKINETIC PARAMETERS IN HUMANS

Address correspondence to: Franco Lombardo, Novartis Institutes for Biomedical

Downloaded from dmd.aspetjournals.org at ASPET Journals on May 10, 2016

PSA = Polar Surface Area

We present herein a compilation and trend analysis of human intravenous

applications including: in silico modelling, in vitro – in vivo scaling, and physiologically-

based pharmacokinetic approaches. Clearance, volume of distribution at steady state,

Downloaded from dmd.aspetjournals.org at ASPET Journals on May 10, 2016

references exclusively from studies utilizing intravenous administration. Plasma protein

data. These parameters were analyzed concurrently with a range of simple

described notions of trends between physicochemical properties and pharmacokinetic

structure-pharmacokinetic relationships and improving our understanding of the

relationship between fundamental chemical characteristics and drug disposition.

The prediction of human pharmacokinetics for new compounds has become an

Downloaded from dmd.aspetjournals.org at ASPET Journals on May 10, 2016

Recently, the availability of computational chemistry methodologies has increased and

To develop computational models for the prediction of human clearance (CL),

intravenously. It is also important that the methods of calculations for reported

pharmacokinetic parameters be done consistently. (For example, values reported

Appendix II of the famous textbook “The Pharmacological Basis of Therapeutics”

Downloaded from dmd.aspetjournals.org at ASPET Journals on May 10, 2016

the development of structure-pharmacokinetic relationships. Hence, many of the

of human pharmacokinetic parameters exclusively from intravenous administration, that

structural attributes to human pharmacokinetic parameters. To the first objective, we

administration. We successfully obtained human intravenous pharmacokinetic data for

database is reported herein and also provided in tabular format as supplemental

of use to scientists seeking to develop computational models and correlative approaches

to the prediction of human pharmacokinetics of new compounds. For the second

objective, we have examined the relationships between human intravenous

Downloaded from dmd.aspetjournals.org at ASPET Journals on May 10, 2016

construction should be of considerable use to scientists involved in the discovery of new

fundamental pharmacokinetic parameters. The pharmacokinetic data included in this

Downloaded from dmd.aspetjournals.org at ASPET Journals on May 10, 2016

volume of distribution. For this database, we sought the steady-state volume of

following equations depending upon what was reported:

Downloaded from dmd.aspetjournals.org at ASPET Journals on May 10, 2016

the paper, then the equation:

Dose • AUMC 0-∞

pharmacokinetics. In these instances, plots of plasma concentration vs. time included in

from intravenous administration and if they were specifically described as steady-state

Downloaded from dmd.aspetjournals.org at ASPET Journals on May 10, 2016

patient populations and/or populations taking concomitant medications (e.g. cancer

especially drug-drug interaction studies and studies comparing healthy individuals to

Downloaded from dmd.aspetjournals.org at ASPET Journals on May 10, 2016

bioavailability. In these instances, the pharmacokinetic parameters from the intravenous

were weight-averaged by number of subjects.

For compounds possessing adequate intravenous pharmacokinetic data, the

no published protein binding data could be found.

The physicochemical parameters calculated for all compounds and described in

SciFinder (2007), generated via version 8.14 of the ACDLabs software.

Downloaded from dmd.aspetjournals.org at ASPET Journals on May 10, 2016

Characteristics of the Pharmacokinetic and Physicochemical Values. Through extensive

Downloaded from dmd.aspetjournals.org at ASPET Journals on May 10, 2016

extensive level of tissue partitioning.

Plasma clearance values ranged from 0.0037 (7-hydroxystaurosporine) to 1070

mL/min/kg, respectively. Approximately three-fifths of the compounds resided in a

mechanisms in these cases, or blood-to-plasma ratios in excess of unity. Many of the

compounds are prodrugs or drugs in which pharmacologically active metabolites are