Pharmacokinetics -- part 1 -- W.M. Tom Department of Pharmacology University of Hong Kong 1 1 1 1

Pharmacokinetics elimination -- metabolism & excretion -- refers to the action of the body on the drug, including: absorption distribution elimination -- metabolism & excretion 1 1 1 1

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Drug Disposition

Drug Absorption Peroral administration (P.O. route) swallowing commonly known as “oral administration” most convenient and economic method of systemic drug delivery dosage forms, e.g. tablets, capsules, syrups, etc. 1 1 1 1

Drug absorption Solids are not absorbed! Dissolution is usually the rate limiting step!

Drug Absorption Peroral administration (P.O. route) drug release  formulation (e.g. tablets) e.g. particle size, surface area, excipients (inert substances) DISINTEGRATION (solid )  DISSOLUTION (solution) ABSORPTION SYSTEMIC CIRCULATION (% bioavailability) 1 1 1 1

Drug absorption stomach (pH 1~3) in favour of weak acid absorption duodenum (pH 5~7) in favour of weak base absorption ileum (pH 7~8) in favour of weak base absorption 1 1 1 1

Diffusion Across Membrane (pH < pKa ) HA Weak Acid (pH > pKa ) A- (pH > pKa ) B Weak Base (pH < pKa ) BH+

Drug Absorption Factors affecting drug absorption by enteral routes 1. Drug dissolution -- depends on drug formulation of oral preparations 2. pH environment in GI tract -- unionized form efficiently absorbed 3. Lipid solubility of the drug -- nonpolar form easily absorbed 1 1 1 1

Drug Absorption Factors affecting drug absorption by enteral routes 4. Effects of food -- in general delays drug absorption 5. First pass effect -- absorption of a drug into the portal circulation -- drug metabolized by liver before it reaches the systemic circulation 1 1 1 1

First-pass effect mouth esophagus stomach small intestine colon rectum 1 1 1 1

First - Pass Effect 1 1 1 1

Drug Absorption Parenteral routes 1. intravenous injection (IV) -- directly into a vein -- 100% bioavailability 2. intramuscular injection (IM) -- into a muscle -- depends on blood supply 1 1 1 1

Drug Absorption Parenteral routes 3. subcutaneous injection (SC) -- under the skin -- intended for slow absorption 4. others -- inhalation -- sublingual -- topical -- transdermal, etc. 1 1 1 1

Absorption, distribution, metabolism and excretion 1 1 1 1

Drug Distribution Drug transfer to various tissues -- depends on drug lipophilicity and blood flow Drug barriers -- e.g. blood-brain barrier, placenta Drug binding to plasma proteins -- bound drugs are pharmacologically inactive -- unbound drugs are free to distribute to target tissues -- different drugs may compete for binding to plasma proteins and displace each other from binding sites 1 1 1 1

Free Drug Bound Drug LOCUS OF ACTION “RECEPTORS” TISSUE RESERVOIRS ABSORPTION Free Drug EXCRETION SYSTEMIC CIRCULATION Bound Drug BIOTRANSFORMATION

Saturation of Protein Binding Sites

Drug displacement from protein binding sites

Plasma Protein Binding consequence of drug displacement an increase in free drug concentration of the displaced drug  an increase in drug effect (be cautious when using a drug of low T.I.) a decrease in the duration of action of the displaced drug because more free drugs are available for elimination 1 1 1 1

Drug Metabolism modification of the chemical structure by enzyme systems in the body -- e.g. cytochrome P450 in liver these chemical reactions produce water-soluble metabolites which are more readily excreted by the kidneys -- phase I reaction, e.g. oxidation -- phase II (conjugation) reaction, e.g. glucuronidation drug metabolism activity can be influenced by a variety of drugs 1 1 1 1

The two phases of drug metabolism 1 1 1 1

The two phases of drug metabolism 1 1 1 1

Proportion of drugs metabolized by the major phase I and phase II enzymes 1 1 1 1

Drug Metabolism enzyme induction -- results in faster rate of metabolism -- e.g. in heavy cigarette smokers, alcoholics enzyme inhibition -- results in slower rate of metabolism -- e.g. taking another drug which uses the same enzyme for metabolism biological variations in drug metabolism -- e.g. genetics, disease states, age, etc. 1 1 1 1

Drug Excretion in urine -- by glomerular filtration and renal tubular secretion -- polar water-soluble metabolites readily excreted while nonpolar forms reabsorbed back to circulation in bile and feces other routes -- e.g. in sweat, milk and other body fluids -- volatile gases by exhalation 1 1 1 1

Renal excretion of drugs -- lipid-soluble and un-ionized drugs are passively reabsorbed through the nephron -- active secretion of organic acids and bases occurs only in the proximal tubular segment -- in distal tubular segments, the secretion of H+ favours reabsorption of weak acids (less ionized) and excretion of weak bases (more ionized) 1 1 1 1

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Pharmacokinetics -- part 2 -- W.M. Tom Department of Pharmacology University of Hong Kong 1 1 1 1

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Time course of action of a single oral dose Time of onset = T1 - T0 Time to peak effect = T2 - T0 Duration of action = T3 - T1 MEC = minimum effective concentration 1 1 1 1

Time course of drug action time of onset -- the time taken for the drug to produce a response time to peak effect -- the time taken for the drug to reach its highest blood concentration duration of action -- the time during which the drug produces a response elimination half-life ( t 1/2 ) -- the time taken to reduce the drug concentration in the blood by 50% 1 1 1 1

One Compartment IV Bolus Pharmacokinetic Model Assumptions drug is mixed instantaneously in blood drug in the blood is in rapid equilibrium with drug in the extravascular tissues drug elimination follows first order kinetics 1 1 1 1

One Compartment IV Bolus Pharmacokinetic Model rate of concentration change at each time point: dCp ——— = – k • Cp dt …. (1) Cp : plasma drug concnetration k : elimination rate constant 1 1 1 1

One Compartment IV Bolus Pharmacokinetic Model Ct = C0 • e – k • t ………. (2) Ct : plasma concentration at time t C0 : plasma concentration at time 0 1 1 1 1

One Compartment IV Bolus Pharmacokinetic Model k • t log Ct = log C0 – ————— ………. (3) 2.303 Ct : plasma concentration at time t C0 : plasma concentration at time 0 1 1 1 1

One Compartment IV Bolus Pharmacokinetic Model Apparent volume of distribution (Vd ) apparent volume that the drug is distributed into not a physiological volume amount of drug in the body X Vd = ———————————— = —— drug conc. In plasma Cp DOSE or Vd = ————— ………………. (4) C0 1 1 1 1

One Compartment IV Bolus Pharmacokinetic Model DOSE Vd = ————— ………………. (4) C0 substitute (4) to (3), I.e. Ct = C0 • e – k • t Ct = ————— • e – k • t ………. (5) Vd 1 1 1 1

One Compartment IV Bolus Pharmacokinetic Model Half-Life of Elimination ( t 1/2 ) time taken for the plasma concentration to fall to half its original value 0.693 t 1/2 = ————— ………………. (6) k 1 1 1 1

One-compartment pharmacokinetics (single dose, IV) Cp = plasma drug concentration C0 = plasma concentration at time zero k el = elimination constant elimination half-life t 1/2 = t 2 - t 1 1 1 1 1

One Compartment IV Bolus Pharmacokinetic Model Drug clearance ( CL ) a measure of he efficiency with which a drug is removed from the body rate of elimination amount of drug • k CL = ———————— = ————————— Cp Cp = Vd • k ………………. (7) CL total = CL kidney + CL liver + CL others 1 1 1 1

One Compartment IV Bolus Pharmacokinetic Model Bioavailability ( F ) measures the extent of absorption of a given drug, usually expressed as fraction of the administered dose intravenous injection, by definition, has a bioavailability of 100% AUC • CL F = —————————————— ….. (8) DOSE AUC : area under the conc.-time curve 1 1 1 1

Bioavailability i.v. route (AUC)o (AUC)iv oral route Time (hours) Plasma concentration i.v. route (AUC)o (AUC)iv oral route Time (hours)

Multiple IV Bolus Dose Administration drug accumulation occurs when repeated doses are given before the drug is completely eliminated repeated drug administration at dose intervals (t ) will give a steady state with the plasma concentration fluctuating between a maximum (Cmax) and a minimum (Cmin ) value 1 1 1 1

Plateau principle Css = steady state concentration Cmax = maximum Css Cmin = minimum Css MEC = minimum effective concentration MTC = minimum toxic concentration therapeutic range = MTC - MEC 1 1 1 1

Time course of drug action plateau principle -- repeated drug administration at fixed dosage intervals will produce a plateau concentration of drug in the blood (I.e. steady state) steady state -- a state at which the rate of drug administration is equal to the rate of elimination therapeutic range -- the range between the minimum effective concentration (MEC) and the minimum toxic concentration (MTC) of a drug 1 1 1 1

Effect of dosage intervals on drug concentration curve 1 -- dosage interval too short; curve 2 -- too long; curve 3 -- ideal 1 1 1 1

Blood levels of drugs with intermittent dosage a typical oral dosage four times a day on a schedule of 10-2-6-10 or 9-1-5-9 1 1 1 1

Time course of drug action loading dose -- a large dose given to achieve therapeutic concentration rapidly maintenance dose -- a dose given to maintain the drug concentration at steady state 1 1 1 1

Combined Infusion and Bolus Administration to achieve a therapeutic concentration more quickly is to give a loading dose by rapid IV injection and then start the slower maintenance infusion Loading dose = Css  Vd ........... (9) Maintenance dose = CL  Cp   ………. (10) 1 1 1 1

Multi-compartment Pharmacokinetic Model the drug appears to distribute between 2 or more compartments the drug is not instantaneously equilibrated in various tissues rapidly perfused tissues often belong to the central compartment slowly perfused tissues belong to the peripheral compartment 1 1 1 1

Two-compartment pharmacokinetics (single dose, IV) Two-compartment pharmacokinetics (single dose, IV) central compartment (rapid) t 1/2  peripheral compartment (slow) t 1/2  1 1 1 1

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