Pharmacokinetic effects on human and fetus

Study and characterization of the time course of drug absorption, distribution, metabolism and excretion, and the relationship of these processes to the intensity and time course of therapeutic and toxicology effects of drug. It describes the processes whereby a drug administered by a specific mode and in a specific dose is handled by the body, leading to specific drug concentrations in different tissues/organs. Part of drug will reach site(s) of action and exert its pharmacodynamic action. Another way it can be said as what body does to drug. Pharmacokinetics is used in the clinical setting to enhance the safe and effective therapeutic management of the individual patient. This application has been termed as Clinical Pharmacokinetics

 The time course of drug concentration in the body after its

administration can be defined by a number of pharmacokinetic parameters.  Information on pharmacokinetics of one drug helps in anticipating the pharmacokinetics of another  The knowledge of pharmacokinetic behavior of one drug coupled with important pharmacodynamic parameters like therapeutic index have several applications  Drug therapy is a dynamic process. When a drug product is administered, absorption continues for a finite period of time and distribution, metabolism, and excretion of drug continues at various rates.

 Normally, the aim of a drug therapy is to achieve and maintain

effective concentration of drug at the receptor site.  However, as the body constantly tries to eliminate the drug, it is necessary to balance absorption against elimination to maintain the desired concentration.  Often the receptor site are tucked away in a specific organ or tissue of the body, i.e., CNS, and it is necessary to depend on the blood supply to distribute the drug from the site of administration, such as GIT, to the site of action.

 To achieve the goal by overcoming those processes and

barrier, development of proper drug delivery system is most important.  The development of drug delivery system is extremely complex and interwoven, and it requires a team approach. Pharmacokinetic and biopharmaceutical aspects are very important in this endeavor.  Basic pharmacokinetic understanding of a given drugs disposition in human body is essential for proper design of delivery systems.

 Pharmacokinetic

principles are being applied by clinicians to the rational design of dosage regimens.  It has become more relevance due to stringent regulatory requirements.  Pharmaceutical dosage form design, thus, must be based on a sound knowledge of the pharmacology, physico-chemical properties, pharmacokinetics, pharmacodynamics of the drug and regulatory requirements.

Application of Pharmacokinetics
Design and Drug Development with greatly improved therapeutic effectiveness and fewer or no toxic effects Design and Drug Development of an optimum formulation for better use of the drug. Design and Drug Development of controlled/ targeted release formulation Select appropriate route of drug administration Select the right drug for a particular illness. Predict and explain drug-food and drug-drug interactions Deciding appropriate multiple Dosage Regimen Deciding Rational Dose, Frequency And Duration Therapeutic drug monitoring in individual patients ADME Study, Bioavailability Or Bioequivalence Studies Dosage adjustments in situations of altered physiology and drug interactions. Pharmacokinetics – Pharmacodynamics Relationship.

The applications of pharmacokinetic principles are mainly aimed at achieving the therapeutic objective. It is often control or cure of the condition in shortest possible time with minimum side effects by use of least amount of drug.

Phamacokinetic Parameters
Overall first order elimination rate constant (K) Half life ( t ½ ) Clearance (Total, Renal, Hepatic, etc.) (Cl) Effective concentration range Absorption rate constant ( Ka ) Extent of bioavailability ( F ) Fraction of dose excreted unchanged in urine ( Xu∞ ) Blood – plasma concentration ratio Apparent volume of distribution ( Vd ) Fraction of protein binding (Fb) Peak concentration (Cp) Time to reach peak concentration (tp ) Toxic concentrations

K4 Drug at Absorption site Ka Drug in Blood K1 K-1

Drug in Urine K5 K6 K-2 Drug in Other Excretory Fluids Metabolite(s)


Drug in Other Fluids of Distribution


Drug in Tissues

Schematic representation of drug absorption, distribution, and elimination

Absorption: Absorption is defined as the process by which unchanged proceeds from site of administration to site of measurement within the body. Absorption is not restricted to oral administration. It occurs as well following intramuscular, subcutaneous, and other extravascular routes of administration. Monitoring intact drug in blood or plasma offers a useful means of assessing the entry of drug into the systemic circulation. There are several possible sites of loss. GI lumen, liver, muscle, tissues (sites of administration). The loss as drug passes, for the first time, through sites of elimination, such as the GI membranes and the liver, during absorption is termed as first-pass effect.

Distribution: The transfer of drug from blood to extravascular fluids (i.e., extra-cellular and intracellular water) and tissues is called distribution. Drug distribution is usually a rapid and reversible process. Drug in the plasma exists in a distribution equilibrium with drug in the erythrocytes, in other body fluids and in tissues. Changes of plasma drug concentration are indicative of changes in drug level in other tissues including sites of pharmacologic effect.

Metabolism: It is the biochemical (enzymatic) conversion of a drug to another chemical form. Many tissues in the body are capable of metabolizing drugs, but most drugs are mainly metabolized in the liver by enzymes localized in hepatic microsomes. Drug-metabolizing enzymes oxidize, reduce, hydrolyze, or conjugate compounds. Reduction, oxidation, and hydrolytic reactions (phase I pathways) result in metabolites with functional groups (hydroxyl, amine, or carboxyl) that can be conjugated (phase II). In man the most common conjugation of drugs or metabolites occur with acetate, sulfate, glycine, or glucuronic acid.

Elimination: It is the irreversible loss of drug from the site of measurement. The transfer of drug from the blood to the urine or other excretory compartments (i.e., bile, saliva, sweat, milk, etc.) and the enzymatic or biochemical transformation of drug in the issues or plasma to metabolic products, are usually irreversible processes. The net result of these irreversible steps is called drug elimination. Elimination occurs by two processes , excretion and metabolism. Elimination processes are responsible for the physical or biochemical removal of drug from the body

 Excretion: It is the irreversible loss of chemically
unchanged drug by various routes. This can occur through urine, biliary secretion, saliva, sweat, milk, respiratory route. Routes of excretion and extent of excretion by any route may vary from drug to drug depending on nature and physicochemical properties of drugs.

Factors Influence Drug Absorption
Biological Factors Physicochemical Factors Formulation Factors

Biological Factors
Gastrointestinal Physiology Anatomy GIT Gastrointestinal Blood Flow Gastrointestinal pH Gastric Emptying and Gastrointestinal Motility GIT Contents: acids, enzymes, mucin, bile salts Effects of Food/Diet on Drug Absorption Presence of other drugs Routes of administration

Physicochemical Factors
Drugs pKa and Gastrointestinal pH Lipid solubility and Partition coefficient Dissolution and pH Diffusion Layer pH Salts Soluble Prodrugs Surface area and particle size Crystal form Drugs stability at site of absorption Complexation Adsorption Viscosity

Formulation Factors
Dosage Forms: Solutions Suspensions Capsules Tablets Coated Tablets Enteric-coated Tablets CR formulations Targeted or site specific formulaitons

 Drug Distribution encompasses


Distribution in Blood and other fluids Cellular Distribution Drug Penetration in CNS Placental Transfer of Drugs Blood Flow It is expressed by Distribution Volumes (Vd) Drug binding at different places is very important  Drug Binding in Blood • Plasma protein binding and drug distribution • Plasma protein binding and drug effect • Plasma protein binding and elimination  Drug Binding in Tissues  For designing novel delivery systems knowledge distribution characters is very important and useful.


Factors Affecting Metabolism
Genetic Variation Environmental Determinants Inhibition of drug metabolism Induction of drug metabolism Disease Age and Sex Body Weight and Size Obesity Pregnancy

 Drug Excretion
Renal Excretion Glomerular filtration, Tubular secretion, Tubular reabsorption Renal Clearance Biliary Excretion Salivary Excretion Secretion of drugs into milk Other excretion

Pharmacokinetic characterization of drugs for selection of suitable delivery systems
          

compartment model elimination rate constant or terminal half-life(t ½) Area under the concentration-time curve(AUC) Total clearance (ClT) Apparent volume of distribution (Vd) Mean steady state concentration (Css ) Mean residence time First-pass effect Intrinsic absorption rate constant Relative areas Dosage form index

Important biopharmaceutical characters of drug for developing delivery system
 Molecular weight  pKa  Isoelectric point  Solubility  Apparent partition coefficient  Extent of protein binding  Extent of α1 – acid glycoprotein binding  Erythrocyte uptake  General absorbability  Biopharmaceutical aspects for route of administration

Design of Controlled Release formulation
CT is the target concentration to be maintained for T hr Rate of Elimination = K. CT.Vd or 0.693 CT.Vd t1/2 Where K is elimination rate constant of the drug Vd is apparent volume of distribution . Rate of absorption, Ka.Xa should be equal to rate of elimination to maintain constant concentration. So, Ka. Xa = K. CT. Vd Then rate of release should be equal to rate of absorption and rate of elimination. So rate of release, Kr = K. CT.Vd

So, Maintenance dose = rate of release x duration to be maintained = K. CT. Vd.T tmx a


Lg o


Ka-K K where Ka is absorption rate constant
L a in d s o d g oe

CT.V eKt max

F where F is bioavailability (fraction) P.S: Above is on the basis that drug confers one compartment distribution.

Equation to express plasma concentration of CR product administered

Ko (e-KT-1)e-Kt

VK Where Ko is Zero order release rate ‘T’ is time of total release ‘t’ is anytime at which concentration is measured. ‘t’ can b less than or equal or more than ‘T’

Site specific Delivery
P-DTO Target Organ

DTO Target Organ

k’13 P-D kinput

k’31 k2


DCC Central Compa rtment

P-DCC Central Compa rtment




P-DTC Tissue Compa rtment

k3 Scheme 3



DTC Tissue Compa rtment

Drug Targeting
(D) +(QC) (D-DHC)BA R IN +

Chemical Coupling BBB

(D-QC)+ Reduction



Oxidation (D-QC)+

Enzymatic cleavage


Oxidation (D-QC)+



(D) +(QC)+|
K 4

(D) +(QC)+|


Important Considerations
 Ideally, drug delivery systems should be designed on the basis of a knowledge of the desired timeprofile of drug response.  It is important to establish the relationship between in vivo and in vitro profiles (IVIVC) in order to optimize the formulation and for quality control purposes.  These objectives require a reliable method for estimating the rate of bioavailability of the drug from the delivery system.

Pharmacokinetics Evaluation of Novel Delivery Systems in vivo.
The in-vivo evaluation of delivery devices involves two basic questions  Is the desired rate-time profile of release as shown in vitro actually obtained in vivo?  Is the desired response-time profile obtained in-vivo? To answer the first, four approaches are there  Assay of unreleased drug.  Assay of parent drug and/or metabolite in blood, plasma, or serum.  Assay of parent drug and/or metabolite in excreta  Quantity of response intensity.

Second question can be answered if pharmacological or clinical response can be quantified directly (like blood pressure, dilation of pupils, intraocular pressure, urinary output, electrolyte excretion, blood glucose levels, etc). Otherwise long range clinical studies are required. The selection or choise of a suitable method for estimating drug input rate and pharmacodynamic effect is very important.

Pharmacokinetic Consideration of Site- Specific Drug Delivery Systems
 Objective of drug targeting is to deli er a drug to

its site of action and at the same time, minimize any toxic effects. In pharmacokinetic terms, it aims to maximize the ratio of drug concentration at its site of action to that at site of potential toxicity.  The evaluation can be done by: - Steady state analysis - Pharmacodynamic aspects - Temporal aspects

Steady state analysis



Drug targeting index (DTI) AUCR/AUCT (drug carrier admin.) DTI = -----------------AUCR/AUCT (drug admin.) AUC is area under the concentration time profile

Pharmacodynamic aspects: AUIT (drug administration) Target Index, TI = -------AUIT (drug carrier admins.) AUI stands for area under the intensity-time profile Temporal aspects: MIR/MIT(drug carrier adm)

MI (Max. Intensity) = -------------MIR/MIT(drug adm)

It is very important to have complete knowledge of pharmacokinetic characters of drug and factors affecting them to have complete knowledge/study for designing an effective and useful drug delivery systems. Pharmacokinetic study is also important to identify variables that are important in determining the potential success of drug delivery systems. It can be used to evaluate the products or delivery systems Selection/design of proper experimental protocol is very important. Suitable analytical method is necessary for proper estimation. IV-IV correlation and PK/PD relationship are also useful tool for better design.

Suggested References
1. Pharmacokinetics; M.Gibaldi and D. Perrier, Marcel Dekker Inc.; USA; 2nd edition; 1982. 2. Novel Drug Delivery; Eds. L.F.Prescott and W.S.Nimmo; John Wiley & Sons; UK; 1989. 3. Drug Delivery Devices: Fundamentals and Applications; Ed. P.Tyle; Marcel Dekker Inc.; USA; 1988. 4. Biopharmaceutics and Clinical Pharmacokinetics; M. Gibaldi; Lee and Febiger; USA, 4th edition; 1991. 5. Modern Pharmaceutics; Eds. G.S.Banker and C.T.Rhodes; Marcel Dekker Inc.;USA; 3rd edition; 1996. 6. Pharmaceutical Bioequivalence; Eds. P.G.Welling, F.L.S. Tse and S.V.Dighe; Marcel Dekker Inc.;USA; 1991. 7. Novel Drug Delivery Systems; Ed. Y.W.Chien, Marcel Dekker Inc.;USA; 2nd edition, 1992


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