PHARMACOKINETICS.

PHARMACOKINETICS

WHAT THE BODY DOES TO THE DRUG

XENOBIOTIC A compound to which the body is exposed that is foreign to the body. Includes drugs, industrial and environmental chemicals

Pharmacodynamics – concentration – effect
Graded response Quantal response Pharmacokinetics – dose - concentration

Routes of drug administration
Oral Sublingual Rectal Transnasal Intra-tracheal Inhalational Transdermal Subcutaneous Intramuscular Intravenous

Routes of Administration

PHARMACOKINETICS ABSORPTION DISTRIBUTION METABOLISM EXCRETION

ABSORPTION Describes the rate and extent to which a drug leaves its site of administration

Pharmacokinetics Absorption –the process by which the drug moves into the body from external source

Absorbed through the skin
Drug Absorption Orally Rectually (drug embedded in a suppository, which is placed in the rectum) Parenterally (given in liquid form by injection with a needle and syringe) Inhaled –thru the lungs as gases, as vapors, or as particulars carried in smoke or in an aerosol Absorbed through the skin Absorbed through mucous membranes (from snorting or sniffing the drug, with the drug depositing on the oral or nasal mucosa)

Drug Absorption -caveats
Orally Drug must be soluble and stable in stomach fluid (not destroyed by gastric acids), enter the intestine, penetrate the lining of the stomach or intestine, and pass into the blood stream.

Drug Absorption -disadvantages
May occasionally lead to vomiting and stomach distress. How much of the drug will be absorbed into the bloodstream cannot always be accurately predicted because of the genetic differences between people and because differences in the manufacture of the drugs. The acid in the stomach destroys some drugs.

Drug Absorption -caveats
Rectually Rarely used unless patient is vomiting, unconscious, or unable to swallow

Rectually Often irregular, unpredictable, and incomplete Many drugs irritate the membranes that line the rectum.

Intravenous –directly into a vein Intramuscular –directly into muscle
Drug Absorption Parenterally Intravenous –directly into a vein Intramuscular –directly into muscle Subcutaneous –just under the skin

Drug Absorption Parenterally Often produces a more prompt response than does oral administration because absorption is faster. Permits a more accurate dose because the unpredictable processes of absorption are bypassed.

Parenterally Leaves little time to respond to an unexpected drug reaction or accidental overdose. Requires the use of sterile techniques. Once a drug is administers by injection, it cannot be recalled. Drugs that cannot become completely soluble before injection, cannot be injected intravenuously.

Relatively quick route to the brain.*
Drug Absorption Inhaled Lung tissues have a large surface area with large blood flow, allowing for rapid absorption of drugs. Relatively quick route to the brain.* *May even have a faster onset of effect than drugs administered intravenously.

Absorbed through the skin Provides continuous,
Drug Absorption Absorbed through the skin Provides continuous, controlled release of a drug from a reservoir through a semipermeable membrane. Potentially minimizes side effects associated with rapid rises and falls in plasma concentration of the drug contained in the patch.

CHARACTERISTICS OF A DRUG FAVORING ABSORPTION
Low molecular size Nonpolar Uncharged High lipid solubility

MECHANISMS OF SOLUTE TRANSPORT ACROSS MEMBRANES
Passive diffusion Facilitated diffusion Active transport Endocytosis

Passive Diffusion Concentration gradient
Lipid-water partition coefficient Area, Thickness and Permeability of the membrane Ionic, pH, charge gradient*

Ionic Transport pH gradient Drug’s acid dissociation constant (pKa)

pKa – pH value at which one half of the drug is present in ionic form
pKa = pH + log (HA) (A-)

Henderson-Hasselbalch equation
Calculates the ratio of non-ionized to ionized drug at each ph pH = log [A-] pka (Acid) [HA] or = log [B] + pKa (Base) [BH+] Ka = dissociation constant A = molar concentration of the acidic anion HA = molar concentration of the undissociated acid B = molar concentration of the basic anion HB = molar concentration of the undisscociated base

Many drugs are weak acids or weak bases
Drugs and ionisation : Theory Many drugs are weak acids or weak bases Acids =aspirin, barbiturates Bases =propranolol, opioids The pKa of a drug is the pH at which it is 50% ionised and 50% unionised aspirin has pKa of 3.5 : at an acid pH of 3.5 it is 50% U/I propranolol has a pKa of 9.4 : at a basic pH of 9.4 it 50% U/I

Drugs and ionisation : Theory
The more acidic the pH for an acidic drug the more of it is unionised, and vice versa for a basic drug The U fraction is lipid soluble and thus crosses cell membranes more easily than the I fraction

Drugs and ionisation: Which of the following statements are correct
Drugs and ionisation: Which of the following statements are correct? Explain briefly 1. Ionised drugs do not easily cross lipid barriers such as the gut, placenta and blood brain 2. Acidic drugs are well absorbed in the acidic medium of the stomach, basic drugs in the alkaline medium of the small bowel

Characteristics of Un-ionized and Ionized Drug Molecules
Un-ionized Ionized Pharmacologic effect Active Inactive Solubility Lipids Water Cross lipid barriers Yes No (gastrointestinal tract, blood-brain barrier, placenta) Hepatic metabolism Yes No Renal excretion No Yes

Drugs and ionisation: Practise
Acidic drugs (such as aspirin) will be ionised in an alkaline urine and thus cannot be reabsorbed across the renal tubular membrane (alkaline diuresis) pH trap (ion trapping) is significant for some drugs, especially local anaesthetics in labor

Factors Affecting DRUG ABSORPTION
Biopharmaceutic Factors - Tablet compression - Coating and Matrix - Excipients Interactions - Food - Other Drugs - Bacteria Physiological Factors

Factors Affecting GI Absorption
Gastric Emptying Time Intestinal Motility Food Formulation Factors “First Pass Effect”

PK Definitions Plasma Concentration Time Postdose (hr)
Cmax: Maximum concentration – may relate to some side effects 10000 AUC: Area under the curve (filled area) = overall drug exposure 3000 1000 Plasma Concentration Cmin: minimum or trough concentrations: may relate with efficacy of HIV drugs 100 2 4 6 8 10 12 Time Postdose (hr)

Drug Levels & Resistance

BIOAVAILABILITY Quantity of drug in systemic circulation
Quantity of drug administered

Bioavailability BIOAVAILABILITY is the fraction of the oral (rectal) dose reaching the systemic circulation High bioavailability means good absorption and limited liver metabolism Are these two properties compatible?

Bioavailability Oral and rectally administered drugs are absorbed via the gut wall into the portal circulation The liver (and gut wall) removes drugs by ‘first pass’ metabolism and binding so only a proportion reaches the hepatic veins and the systemic circulation

Bioavailability Lipid soluble drugs such as propranolol are well absorbed but have high ‘first pass’ and hepatic extraction ratio (thus low oral bioavailability) versus water soluble drugs such as digoxin 2. Which pharmacokinetic parameter most reliably reflects the amount of drug reaching the target tissue after oral administration? 1. How do you measure bioavailability?

Measuring bioavailability
I.v. dose Log Concentration Bioavailability = AUC I.v. AUC oral/ AUC i.v. Oral dose AUC oral time

Bioavailability (f) f = dose(IV) x AUC (PO)/dose(PO) x AUC (IV)

Why do we need to know the bioavailability of a drug?
e.g. i.v. versus i.m., oral versus rectal To determine the correct route of administration To determine the correct dosage

DISTRIBUTION Delivery of drug from systemic circulation to tissues

Pharmacokinetics Distribution –the drug is distributed throughout the body (including fetus)

Distribution The movement of drug from the blood to and from the tissues

Drug Distribution 4 Body Membranes that Affect Drug Distribution
1. Cell membranes 2. Walls of the capillary vessels in the circulatory system 3. Brain-blood barrier 4. Placental barrier In the case of a psychoactive drug, most of the drug circulates outside the brain and therefore does not contribute directly to its pharmacological effects {this means that to get even a small amount of the drug to our brain, we may have to flood the rest of our bodies with it –which can cause terrible side effects like organ failure}. Indicates that drugs that bypass the stomach bypass these enzymes and are metabolized differently.

Drug Distribution 1st Body Membrane that Affects Drug Distribution
Cell membranes Permeable to small lipid (fatty) molecules Indicates that drugs that bypass the stomach bypass these enzymes and are metabolized differently.

Drug Distribution 2nd Body Membrane that Affects Drug Distribution
Walls of the capillary vessels in the circulatory system Does not depend on lipid solubility Only drugs that do not bind to plasma proteins pass through capillary pores. Indicates that drugs that bypass the stomach bypass these enzymes and are metabolized differently.

Drug Distribution 3rd Body Membrane that Affects Drug Distribution
Brain-blood barrier The rate of passage of a drug into the brain is determined by two factors: (1) the size of the drug molecule and (2) its lipid (fat) solubility. Indicates that drugs that bypass the stomach bypass these enzymes and are metabolized differently.

Drug Distribution 4th Body Membrane that Affects Drug Distribution
Placental barrier Oxygen and nutrients travel from the mother’s blood to that of the fetus, while carbon dioxide and other waste products travel from the blood of the fetus to the mother’s blood. Fat-soluble substances (including all psychoactive drugs) diffuse rapidly and without limitation. Indicates that drugs that bypass the stomach bypass these enzymes and are metabolized differently.

PATTERNS OF DRUG DISTRIBUTION
Mainly in the vascular system ex. Dextran, highly bound to plasma protein apparent Vd = 3-5 L in adults (approx plasma volume)

Uniformly distributed throughout the body water ex.ethanol, sulfonamides Vd = L corresponding to total body water

Concentrated specifically in one or more tissues that may or may not be the site of action Vd – very large values ex. Chloroquine – 1000x in the liver Tetracycline – bone and developing teeth

Non-uniform distribution in the body - highest concentrations usually in the liver, kidney and intestine - distribution varies with lipid solubility, ability to pass thru membranes

Factors Affecting Drug Distribution
Affecting Rate of Distribution Membrane Permeability Blood Perfusion Affecting extent of distribution Extent of plasma protein binding Regional differences in pH Lipid solubility Available transport mechanisms Intracellular Binding

Membrane Permeability
Capillary permeability Renal capillary permeability large pores Brain capillaries

Blood Perfusion Rate Greatest blood flow – brain, kidneys, liver and muscle Highest perfusion rate – brain, kidneys, liver, heart Thiopental – partly ionised, perfusion limited; penicillin – polar, slowly permeable; permeability limited transfer

Protein Binding Extensive plasma protein binding – lower Vd; stay in central blood compartment Slight change in the binding of highly bound drugs – significant change in clinical response Only free drug are active

Acidic drugs (e.g. barbiturates) bind to albumin
Plasma protein binding of drugs Acidic drugs (e.g. barbiturates) bind to albumin Basic drugs (e.g. opioids, local anaesthetics) bind to alpha 1 acid glycoprotein The process is reversible Binding sites are non-selective for similar drugs and thus one can displace another

Plasma protein binding of drugs
The bound drug is inactive whilst bound and this limits systemic distribution and glomerular filtration Only drugs which are highly bound (>90%) with small Vd are affected by changes in protein binding (e.g. phenytoin and warfarin)

Drugs Binding sites for acidic agents Vit. C, salicylates, sulfonamides, barbiturates, penicillins, tetracyclines, probenecid Albumin Binding sites for basic agents Quinine, Streptomycin, chloram, digitoxin, coumarin Globulins, 1, 2, β1, β2

Percent Unbound for Selected drugs
Caffeine 90 Digoxin 77 Gentamicin 50 Theophylline 85 Phenytoin 13 Diazepam 4 Warfarin 0.8 Phenylbutazone 5 dicumarol 3

Volume = injected dose/ sampled concentration = 10 litres
Calculating the volume of distribution Injected dose 10 mg. ? Volume of container Sampled concentration 1 mg. l-1 Volume = injected dose/ sampled concentration = 10 litres

Volume = injected dose/ sampled concentration = 100 litres
Calculating the apparent volume of distribution Injected dose 10 mg. ? Volume of container Sampled concentration 0.1 mg. l-1 Volume = injected dose/ sampled concentration = 100 litres

Why do we need to know the volume of distribution?
Vd is needed to calculate the loading dose of a drug (e.g. lignocaine, aminophylline, pethidine, propofol) Loading dose = Vd * effective concentration (Ceff) required Question: What is the loading dose if Vd is 30 litres and Ceff is 10 mg.l-1

Weight consideration Vd is proportional to body weight and thus, the loading dose can be based on body weight Varies with the very young, and very old

Peripheral compartment Central compartment
Two compartment pharmacokinetic model Peripheral compartment K12 Central compartment Dose K21 K elim

Central compartment Intravascular space, highly perfused tissues
Rapid uptake of drug 75% of cardiac output; 10% of body mass Apparent volume can be calculated

METABOLISM Active Drug Inactive drug
Active Drug Active or toxic metabolite Inactive Prodrug Active drug Unexcretable drug Excretable metabolite

Pharmacokinetics Metabolism –detoxification or breakdown of the drug into metabolites that no longer exert any effect

Drug Metabolism Side effects are results that are different from the primary, or therapeutic, effect, for which a drug is taken. First-pass metabolism drug-metabolizing enzymes in either the cells of the GI tract or the liver can markedly reduce the amount of drug that reaches the bloodstream. Indicates that drugs that bypass the stomach bypass these enzymes and are metabolized differently.

BIOTRANSFORMATION Phase I Phase II

PHASE I Modify the chemical structure of a drug OXIDATION REDUCTION
HYDROLYSIS

Oxidative Reactions N- dealkylation – Imipramine, erythromycin
O-dealkylation – Indomethacin,Codeine Aromatic hydroxylation – Phenytoin, phenobarbital N- Oxidation – chlorpheniramine, Dapsone S- oxidation - Cimetidine, Omeprazole Deamination – Amphetamine, Diazepam

75 Liver Microsomal System
Oxidative Reactions: Cytochrome P450 mediated Examples Formation of an inactive polar metabolite Phenobarbital Formation of an active metabolite By Design: Purine & pyrimidine chemotherapy prodrugs Inadvertent: terfenadine – fexofenadine Formation of a toxic metabolite Acetaminophen – NAPQI (N-acetyl-p-benzoquinone imine 75

HYDROLYSIS Ester Hydrolysis – Procaine, aspirin, Succinylcholine
Amide Hydrolysis – Lidocaine, Indomethacin Epoxide Hydrolysis - Carbamazepine

REDUCTION Nitro reduction – Chloramphenicol Dehalogenation – Halothane
Carbonyl Reduction – Methadone, Naloxone

PHASE II Enhance drug’s solubility Enhance excretion rate
Conjugate a drug to large polar molecules to : Inactivate a drug Enhance drug’s solubility Enhance excretion rate

CONJUGATION REACTIONS
Glucoronidation – Acetaminophen, Morphine, Oxazepam Sulfation – Acetaminophen, Steroids Acetylation – Sulfonamides, INH, Clonazepam

Metabolism Induction – drugs can cause an increase in liver enzyme activity thus increasing metabolic rates of some drugs ex. Phenobarbitone – induce metabolism of itself, phenytoin, warfarin Inhibition – inhibit metabolism of other drugs

Liver Drug A inhibits the production of enzymes to metabolize Drug B
Induction Inhibition Liver Drug A induces the body to produce more of an enzyme to metabolized Drug B This reduces the amount of Drug B and may lead to loss of Drug B’s effectiveness This increases the amount of Drug B in the body and could lead to an overdose or toxic effects

Hepatic clearance and extraction ratio
Clearance = Flow X Extraction ratio IF hepatic blood flow = 1500 ml.min-1 and extraction ratio = 50% Clearance = 750 ml. min-1

Extraction ratio = Ci - Co/ Ci
Hepatic clearance and extraction ratio Extraction ratio = Ci - Co/ Ci Ci may be calculated by determining the percentage of a drug absorbed, and thus reaching the liver Co may be calculated from the bioavailability Effect on clearance when hepatic blood flow falls (e.g. hepatic disease, decreased cardiac output and hypovolaemia)

Hepatic microsomal enzymes are capable of being induced and inhibited
Drugs causing induction include barbiturates (i.e.phenobarbitone) rifampicin nicotine and aminophylline Drugs causing inhibition include cimetidine erythromycin metronidazole disulphiram and ethyl alcohol

Effects of hepatic blood flow and enzyme induction/inhibition
Metabolism of high clearance (ER) drugs (e.g. opioids) is more dependent on hepatic blood flow and less dependent of enzyme induction and inhibition

Effects of hepatic blood flow and enzyme induction/inhibition
Metabolism of low to moderate clearance (ER) drug ( e.g. aminophylline) is more dependent on enzyme induction and inhibition and less dependent of hepatic blood flow

Drug metabolism: Zero and first order kinetics
Zero order kinetics: a fixed amount of the drug is metabolised in unit time (e.g. alcohol) First order kinetics: a fixed fraction of the drug is metabolised in unit time

Drug metabolism: Zero and first order kinetics
Most drugs are metabolised by a first order process Amount metabolised is proportional to the concentration of the drug Newborn hepatic metabolism of some drugs such as phenytoin becomes saturable at therapeutic concentrations

It is expressed as the elimination rate constant k, in units of h-1
The rate constant in first order kinetics and relationship to the half life The rate constant is the fractional change in concentration in unit time It is expressed as the elimination rate constant k, in units of h-1 Thus, if 10% of the drug is removed per hour, then the rate constant is 0.1h-1 T1/2 = natural logarithm of 2 (0.693)/k Thus, k of 0.1 = T1/2 of 6.93 hours

Or … the amount metabolised is proportional to the concentration
Clearance First order kinetics states that a fixed fraction of the drug is metabolised in unit time Or … the amount metabolised is proportional to the concentration Or … amount metabolised = K * concentration K is the ‘clearance’ and has the unit of flow (e.g. mls.min-1 or litres.hr-1)

Why do we need to know the drug clearance?
For effective drug therapy you need to be able to maintain the effective concentration (Ceff) that produces the desired effect Thus, we need to calculate the maintenance dose

Why do we need to know the drug clearance?
Maintenance dose = clearance * effective concentration (Ceff) e.g. if clearance is 3 l.hr-1 and Ceff is 10 mg.l-1 Maintenance dose = 30 mg.hr-1 We can thus predict the effect of changes in clearance and Ceff on maintenance dose

CLEARANCE CLP =___rate of elimination (mg/min)______
plasma concentration of drug (mg/ml)

The elimination half life
Half life is the time taken for the concentration (in the plasma) to fall by one half

HALF LIFE AND PERCENT OF DRUG REMOVED (wash out)
Number of Percent of Drug Percent of Drug Half-lives Remaining Removed 0

Half life and onset of action using maintenance dose and no loading dose (wash in)
Number of Percent of final Half-times steady state concentration 0 0

The context sensitive half life
Definition: The time for the plasma concentration to fall by half following steady state infusion and constant blood levels. Usually after several hours infusion.

FACTORS AFFECTING DRUG METABOLISM
Genetic variation Environmental determinants Disease Factors Age Sex Cultural

Metabolism Genetic –people have different amounts of enzymes that metabolize drugs

Metabolism Physiological –if more than one drug is present in the body, the drugs may interact with one another either in a therapeutically beneficial way or in a way that can adversely affect the patient.

Metabolism Environmental –current mood, stress, and past experience with drug can affect metabolism (and toxicity)

ROLE OF CYP ENZYMES IN HEPATIC DRUG METABOLISM
RELATIVE HEPATIC CONTENT OF CYP ENZYMES % DRUGS METABOLIZED BY CYP ENZYMES 102

Examples of substrates
Participation of the CYP Enzymes in Metabolism of Some Clinically Important Drugs CYP Enzyme Examples of substrates 1A1 Caffeine, Testosterone, R-Warfarin 1A2 Acetaminophen, Caffeine, Phenacetin, R-Warfarin 2A6 17-Estradiol, Testosterone 2B6 Cyclophosphamide, Erythromycin, Testosterone 2C-family Acetaminophen, Tolbutamide (2C9); Hexobarbital, S- Warfarin (2C9,19); Phenytoin, Testosterone, R- Warfarin, Zidovudine (2C8,9,19); 2E1 Acetaminophen, Caffeine, Chlorzoxazone, Halothane 2D6 Acetaminophen, Codeine, Debrisoquine 3A4 Acetaminophen, Caffeine, Carbamazepine, Codeine, Cortisol, Erythromycin, Cyclophosphamide, S- and R-Warfarin, Phenytoin, Testosterone, Halothane, Zidovudine Adapted from: S. Rendic Drug Metab Rev 34: , 2002 103

Factors Influencing Activity and
Level of CYP Enzymes Adapted from: S. Rendic Drug Metab Rev 34: , 2002 104

Elimination –metabolic waste products are removed from the body
Pharmacokinetics Elimination –metabolic waste products are removed from the body

Drugs leave the body through: Kidneys Lungs Bile Skin
Elimination Drugs leave the body through: Kidneys Lungs Bile Skin Most drugs leave the body in urine as the unchanged molecule or as a broken-down metabolite of the original drug. *other routes for excreting drugs include the air we exhale, bile, sweat, saliva, and breast milk.*

Drugs leave the body through: Kidneys:
Elimination Drugs leave the body through: Kidneys: 1) Excrete most of the products of body metabolism 2) Closely regulate the levels of most of the substances found in body fluids Psychoactive drugs are often reabsorbed out of the kidneys, so the liver has to enzymatically transform the drugs so with minimal reabsorption they can exit in urine. Most drugs leave the body in urine as the unchanged molecule or as a broken-down metabolite of the original drug.

Drugs leave the body through: Bile
Elimination Drugs leave the body through: Bile After most psychoactive drugs are processed by the liver they are usually less fat soluble, less capable of being reabsorbed, and therefore capable of being excreted in urine. Most drugs leave the body in urine as the unchanged molecule or as a broken-down metabolite of the original drug.

Drugs leave the body through: Lungs
Elimination Drugs leave the body through: Lungs Only occurs with highly volatile or gaseous agents Most drugs leave the body in urine as the unchanged molecule or as a broken-down metabolite of the original drug.

Drugs leave the body through: Skin
Elimination Drugs leave the body through: Skin Small amounts of a few drugs can pass through the skin and be excreted in sweat. Most drugs leave the body in urine as the unchanged molecule or as a broken-down metabolite of the original drug.

Processes That Determine Urinary Excretion of Drug
1. Glomerular filtration 2. Tubular secretion 3. Tubular reabsorption

Drug excretion: Role of the Kidneys

Glomerular filtration (GFR) clearance = fraction unbound (FU) * GFR if TOTAL renal clearance = the above, then the drug is principally excreted by filtration (e.g. gentamicin) AND clearance is proportional to GFR

Passive tubular reabsorption clearance is less than FU * GFR (due to reabsorption) e.g. aspirin and amphetamine (effect of pH of urine) Active tubular secretion (ATS) clearance is greater than FU * GFR (due to secretion) e.g. penicillin (inhibited by probenecid), digoxin (inhibited by quinidine)

Renal Factors that Affect Urinary Drug excretion
Glomerular filtration rate Tubular fluid pH Extent of back-diffusion of unionized form Extent of active tubular secretion of the compound Extent of tubular reabsorption

ADME - Summary

CLINICAL PHARMACOKINETICS

CLEARANCE CLP =___rate of elimination (mg/min)______
plasma concentration of drug (mg/ml)

Clearance First Order Kinetic – constant fraction of the drug in the body is eliminated Saturation Kinetics – constant amount of drug is eliminated per unit time

CLEARANCE: Clinical Utility
Determines the maintenance dose (DM) required to achieve the target plasma conc at steady state DM(mg/h) = Tconcn (mg/L) x Clearance (L/h)

Volume of Distribution
Actual volume in which drug molecules are distributed within the body Vd = D/CO Co = D/Vd

VOLUME OF DISTRIBUTION: Clinical Utility
Used to determine the loading dose (LD) LD = Css x Vd (mg) (mg/L) (L)

HALF-LIFE Time it takes for plasma concentration or the amount of drug in the body to be reduced by 50% t1/2 = (0.693 x Vd) / Cl

HALF-LIFE: Clinical Utility
Determines how long it takes to reach steady state after multiple dosing

CSS = Bioavailability x Dose Interval x Cl
STEADY STATE CONCENTRATION CSS = Bioavailability x Dose Interval x Cl

Initial Concentration
Initial concentration = Loading Dose Vd

Dosing Rate Dosing rate = Target conc’n x Cl / F

Oral Digoxin is to be used as maintenance dose to gradually digitalize a 69 kg patient with congestive heart failure. A steady state plasma concentration of 1.5 ng/ml is selected as an appropriate target. Based on the patient’s renal function, the clearance of digoxin is computed at 1.6/ml/min/kg or 110ml/min.

How should the drug be given in this patient?
Cl – 1.6ml/min/kg F – 70% Target conc’n = 1.5ng/ml

Dosing rate = 1.5ng/ml x 1.6ml.min/kg/0.7

PHARMACOKINETICS.

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