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Gender Has a Small but Statistically Significant Effect on Clearance of CYP3A Substrate Drugs
David J. Greenblatt and Lisa L. von Moltke
J. Clin. Pharmacol. 2008; 48; 1350 originally published online Aug 29, 2008;
DOI: 10.1177/0091270008323754

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Gender Has a Small but Statistically
Significant Effect on Clearance of
CYP3A Substrate Drugs
David J. Greenblatt, MD, and Lisa L. von Moltke, MD
The role of gender on the disposition of drugs metabolized
by cytochrome P4503A (CYP3A) remains controversial.
Some sources suggest that CYP3A activity in women
exceeds that in men, but evidence to support this position
is inconsistent at best. We evaluated 38 data sets in which
clearance of CYP3A substrate drugs was studied in
healthy young male and young female subjects. None of
these drugs was a substrate for transport by P-glycoprotein
(P-gp). The overall mean (±SE) for the female/male ratio of
weight-normalized clearance was 1.26 (±0.07) for par-
enteral dosage and 1.17 (±0.07) for oral dosage. Both
T he possible influence of gender on drug disposi-
tion and response in humans is an issue of med-
ical and public health importance.1,2 The metabolic
fate of drugs biotransformed mainly by cytochrome
P4503A (CYP3A) isoforms has received a great deal
of attention in this context. CYP3A is partially or
entirely responsible for clearance of a large number
of drugs used in clinical practice.3-7 A meaningful
gender-related difference in drug clearance could
imply a corresponding difference in dosage require-
ments and therapeutic standards.
Many reviews of the topic have appeared in the
peer-reviewed medical and scientific literature over
the past 2 decades.8-25 Those reviews specifically eval-
uating gender effects on CYP3A metabolic activity
have come to surprisingly varied conclusions, ranging
From the Department of Pharmacology and Experimental Therapeutics,
Tufts University School of Medicine and Tufts Medical Center, Boston,
Massachusetts. Dr. Hartmut Derendorf acted as editor for this article.
Submitted for publication June 2, 2008; revised version accepted July 1,
2008. Address for correspondence: David J. Greenblatt, MD,
Department of Pharmacology and Experimental Therapeutics, Tufts
University School of Medicine, 136 Harrison Ave, Boston, MA 02111;
e-mail: dj.greenblatt@ tufts.edu.
DOI:10.1177/0091270008323754
1350 • J Clin Pharmacol 2008;48:1350-1355
REVIEW/DRUG METABOLISM
ratios were significantly different (P < .05) from 1.0. For
oral dosage studies, the female/male clearance ratio was
unrelated to the drug’s absolute oral bioavailability. Thus
gender has a small and statistically significant, although
most likely clinically unimportant, influence on CYP3A
phenotype for substrates not transported by P-gp.
Keywords: Gender effects; cytochrome P4503A;
benzodiazepines
Journal of Clinical Pharmacology, 2008;48:1350-1355
© 2008 the American College of Clinical Pharmacology
from “the majority of studies show that apparent
cytochrome P450 (CYP) 3A4 activity is higher in
women than in men”10 to “no major gender-specific
differences seem to exist for . . . CYP3A.”17 The rea-
sons for this variability in interpretation are not clear
but may be related to the scope of the review con-
ducted by each group of authors or to the possibility of
confounding by an indirect effect on CYP3A activity
through transport by P-glycoprotein (P-gp).16,22
To provide additional clarification of this com-
plex topic, we conducted a further review of gender-
related differences in clearance of CYP3A substrate
drugs. The objective was a quantitative analysis of
the magnitude of the male-female differences as well
as the variability among studies. We attempted a
complete review of the available literature on the
topic but with exclusion of P-gp–mediated transport
as a potential confounding factor.
METHODS
Studies cited in previous recent reviews were ini-
tially selected for analysis.16,21,22,25 A number of other
studies published since the appearance of these
reviews, or that were not previously cited, were
 GENDER EFFECT ON CLEARANCE OF CYP3A SUBSTRATE DRUGS
Table I CYP3A Substrates Included in the Review
Adinazolam
Alfentanil
Alprazolam
Bromazepam
Buspirone
Clobazam
Midazolam
Nefazodone
Nifedipine
Nimodipine
Tirilizad
Trazodone
Triazolam
Zolpidem
added. CYP3A substrates also known to be trans-
ported by P-gp (examples: cyclosporine, diltiazem,
erythromycin, quinidine, verapamil) were excluded.
We also excluded drugs for which CYP3A plays a
relatively minor role in clearance (diazepam,
antipyrine) or for which the CYP isoforms mediating
clearance are not clearly identified (chlordiazep-
oxide, desmethyldiazepam, flurazepam). We did not
include studies in which CYP3A phenotype was
determined using urinary excretion data26 or from
“single-point” plasma concentrations.27 Table I
shows the drugs selected for study.
Many studies of gender-related effects of drug
disposition incorporate evaluation of the role of
advanced age.21 In these cases, we used data for
“young” male and female subject groups—generally
with an age maximum of 45 to 50 years. Mean val-
ues of clearance—after normalization for body
weight—were taken from the study results, and the
ratio of clearances (female divided by male) was
analyzed for the present study. In some studies, data
were provided only in graphical form, in which case
we digitized the graph and inferred the numerical
values.
Primary source references are listed in the Appendix.
RESULTS
A total of 38 male/female clearance ratios were avail-
able from the published literature. Of these, 14 ratios
came from parenteral dosage studies (13 intravenous
and 1 intramuscular) and 24 from oral dosage stud-
ies. The parenteral and oral dosage data are not nec-
essarily independent since an intravenous/oral
crossover design was used in a few studies.
REVIEW/DRUG METABOLISM
Figure 1 shows the ratios arrayed in ascending
order. The mean (±SE) ratio for parenteral adminis-
tration was 1.26 (±0.07) (range, 0.88-1.77); for oral
administration, the mean was 1.17 (±0.07), with a
range of 0.52 to 2.13.
Figure 2 shows data for the 2 benzodiazepine
“probe” drugs, midazolam and triazolam. For paren-
teral midazolam, the range of ratios was 0.88 to 1.62,
and for oral midazolam, the range was 0.75 to 1.73.
For oral triazolam, the range was 1.12 to 2.13. It is of
note that both drugs undergo significant presystemic
extraction after oral dosage, and for both, the esti-
mated bioavailability across the enteric mucosa is
approximately 0.5.28-32
DISCUSSION
This analysis indicates that there is not a straightfor-
ward, single answer to the question of whether
gender influences CYP3A metabolic phenotype. On
average, weight-normalized clearance of drugs bio-
transformed mainly by CYP3A is 20% to 30% higher
in young women than in young men. The difference
applies to both parenteral and oral dosage and is not
explained by a confounding effect of P-gp–mediated
transport. Furthermore, there was substantial vari-
ability among drugs, with an overall range of 0.52 to
2.13 in female/male clearance ratios. This might be
explained by differing properties of the drugs under
study, such as variations in hepatic extraction ratio
or net absolute bioavailability after oral dosage.
However, a high degree of variability between studies
still is observed when analysis was focused on a single
specific substrate drug such as midazolam or triazolam.
Also, there was no evident relationship between
absolute oral bioavailability and female/male clear-
ance ratio (Figure 3).
In vitro studies of CYP3A expression and activity
in human liver microsomal samples do not establish
the explanation for gender-related differences insofar
as they exist. While one study asserts a large difference
in CYP3A expression between liver samples obtained
from men and women,33 the majority of published
reports find minimal or no gender differences in
hepatic or enteric CYP3A expression/activity.34-42
In any case, in vitro studies have the intrinsic limi-
tations of confounding due to the time between sample
acquisition and preservation/processing, as well as
the underlying health and pharmacologic exposure
of the tissue donor.
The clinical implications of gender-related differ-
ences in CYP3A phenotype are not certain. Literature
documenting clinical “underdosing” of female
1351
 GREENBLATT AND VON MOLTKE

2.5
I.V./I.M.
ORAL
FEMALE/MALE CLEARANCE RATIO

2.0

MEANS
1.5 I.V./I.M.
Oral

1.0

0.5

Figure 1. Individual female/male clearance ratios for CYP3A substrate drugs (listed in Table I) across a series of 14 studies of parenteral
administration (intravenous [I.V.] or intramuscular [I.M.]) and 24 studies of oral administration. Points are arrayed in ascending order. Also
shown within the box are mean (±SE) values for parenteral dosage (I.V. or I.M.) studies (1.26 ± 0.07) and for oral studies (1.17 ± 0.07).

2.25
FEMALE/MALE CLEARANCE RATIO

2.00

1.75

1.50

1.25

1.00

0.75

0.50

0.25

MIDAZOLAM, MIDAZOLAM, TRIAZOLAM,

I.V. OR I.M. ORAL ORAL

Figure 2. Variability across studies of female/male clearance ratios for parenteral midazolam, oral midazolam, and oral triazolam.

1352 • J Clin Pharmacol 2008;48:1350-1355

 GENDER EFFECT ON CLEARANCE OF CYP3A SUBSTRATE DRUGS

2.25
= ADINAZOLAM
FEMALE/MALE CLEARANCE RATIO

2.00 = ALPROZOLAM
* =
=
BUSPIRONE
MIDAZOLAM
1.75
= NEFAZODONE
= NIFEDIPINE
1.50 = NIMODIPINE
= TRAZODONE
1.25 = TRIAZOLAM
= ZOLPIDEM
1.00 *
0.75

0.50

0.25

0.2 0.4 0.6 0.8 1.0

ABSOLUTE BIOAVAILABILITY OF ORAL DOSAGE

Figure 3. Relation of absolute bioavailability after oral dosage (x-axis) to the female/male clearance ratio (y-axis) for 10 drugs for which
absolute oral bioavailability information is available.

patients is sparse. For the majority of drugs listed in
Table I—as well as other CYP3A substrates concurrently
transported by P-gp—the concentration-response
relationship is not established to an extent that a
20% to 30% male-female difference in systemic expo-
sure attributable to dosage normalized for weight,
but not adjusted for gender, would be clinically
detectable. Further, the dosage of most of these drugs
is not ordinarily normalized for body weight. If a
fixed absolute dose were administered to men and
women, the slightly higher weight-normalized clear-
ance in women would be offset by their lower aver-
age body weight.
This survey has a number of potential limita-
tions. We evaluated only mean values of clearance
within each study. We also did not consider the
potential confounding effects of race/ethnicity, cig-
arette smoking, diet, and CYP3A genotype on net
CYP3A phenotype, although none of these factors
has a consistent or clinically meaningful effect on
drug disposition via CYP3A-mediated metabolism.
In any case, the findings suggest that gender on
average explains only a small proportion of individ-
ual variation in CYP3A phenotype, and that male-
female differences are unlikely to be of clinical
importance. Still, the variability among drugs, and
among studies of the same drug, continues to be
unexplained.
Financial disclosure: Supported in part by grants AG-017880
and AI-058784 from the United States Department of Health and
Human Services.

REVIEW/DRUG METABOLISM 1353

 GREENBLATT AND VON MOLTKE

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