PHARMACOKINETICS 1. Fate of drugs in the body 1.1 absorption M. Kršiak Department of Pharmacology, Third Faculty of Medicine, Charles University in Prague, 2008 1. Fate of drugs in the body 1.1 absorption 1.2 distribution - volume of distribution 1.3 elimination - clearance 2. The half-life and its uses 3. The uses of the half-life 4. Plasma concentration-effect relationship

1. FATE OF DRUGS IN THE BODY WHAT HAPPENS TO DRUGS INSIDE THE BODY Administered ABSORPTION Absorbed DISTRIBUTION „Hidden“ Volume of distribution Eliminated ELIMINATION Clearance Acting

VOLUME OF DISTRIBUTION Depends on: protein binding plasma proteins tissue proteins ONLY A FREE DRUG ACTS! The bound drug is inactive. Free and bound drug are in equilibrium. Displacement: drug-drug interactions

VOLUME OF DISTRIBUTION Vd = Amount of drug in body / Concentration of drug in plasma Because the result of the calculation may be a volume greater than that of the body, it is an APPARENT (imaginary, not actual) volume For example, Vd of digoxin is about 645 liters for a 70 kg man (i.e. about 9 times bigger than his actual volume)

Clinical importance of volume of distribution: When Vd of a drug is big it takes long time to achieve effective plasma concentration of the drug. In such cases a loading dose may be given to boost the amount of drug in the body to the required level. This is followed by administration of lower maintenance dose.

ELIMINATION METABOLIC (biotransformation) ENZYME INDUCTION/ INHIBITION mostly in the liver ENZYME INDUCTION/ INHIBITION oxidase enzymes - cytochrom P450 (CYP2D6 etc) GENETIC POLYMORPHISM EXCRETION kidneys metabolites or unchanged (almost completely unchanged e.g. digoxin, gentamycin) GIT... enterohepatic circulation e.g. tetracyclines

CLEARANCE Clearance (CL) is the volume of plasma totally cleared of drug in unit of time (ml/min/kg) CLtot total CLR renal CLH hepatic CLNR nonrenal (= Cltot - CLR)

and a plate with data Vd= 1000 L, CL = 100 mL/min Bathtube in a hotel with two holes, no plugs, and a plate with data Vd= 1000 L, CL = 100 mL/min http://www.livestrong.com/article/288241-how-to-calculate-your-total-body-volume

2. The half-life and its uses the half-life is the time taken for the plasma concentration to fall by half [plasmatic half-life]

In most drugs after therapeutic doses: plasma concentration falls exponentially Linear kinetics (First order) The rate of elimination is proportional to the concentration [t 1/2 is stable]

In most drugs after therapeutic doses: plasma concentration falls exponentially because elimination processes are not saturated Linear kinetics (First order) Cmax [some robustness to dose increase] Cmin Elimination is the bigger the higher is the level The rate of elimination is proportional to the concentration

Non-linear (Zero-order, saturation) kinetics Elimination processes are saturated e.g. in alcohol, after higher doses of phenytoin, theophyllin Non-linear (Zero-order, saturation) kinetics The rate of elimination is constant For example, in alcohol the rate of metabolism remains the same at about 1 g of alcohol for 10 kg of body weight per hour [unstable t 1/2 ]

elimination is constant, limited In a few drugs at therapeutic doses or in poisoning, elimination processes are saturated Cmax [low robustness to dose increase] Cmin elimination is constant, limited Non-linear (Zero-order, saturation) kinetics

3. The uses of half-life T1/2 as a guide to asses: 1/ At a single-dose: duration of drug action 2/ During multiple dosing: to asses whether a drug is accumulated in the body (it is - if the drug is given at intervals shorter than 1,4 half-lifes) and when a steady state is attained (in 4-5 half-lifes) 3/ After cessation of treatment: to asses the time taken for drug to be eliminated from the body (in 4-5 half-lifes)

[t1/2 = 1 - 2 h] Ampicillin - single dose

THE USES OF THE HALF-LIFE T1/2 as a guide to asses: 1/ At a single-dose: duration of drug action 2/ During multiple dosing: to asses whether a drug is accumulated in the body (it is accumulated if the drug is given at intervals shorter than 1,4 half-lifes) and when a steady state is attained (in 4-5 half-lifes) 3/ After cessation of treatment: to asses the time taken for drug to be eliminated from the body (in 4-5 half-lifes)

„PRINCIPLE OF 4-5 HALF-LIFES“: If a drug is administered in intervals shorter than 1.4 half-life, then a steady state is attained after approximately 4-5 half-lifes The time to attain the steady state is independent of dose. Steady state Plasma concentration t1/2

Why SS is attained after 4-5 half-lifes? Attainment of steady state (SS) during multiple dosing of drug at intervals of 1 half-life

THE USES OF THE HALF-LIFE T1/2 as a guide to asses: 1/ At a single-dose: duration of drug action 2/ During multiple dosing: to asses whether a drug is accumulated in the body (it is - if the drug is given at intervals shorter than 1,4 half-lifes) and when a steady state is attained (in 4-5 half-lifes) 3/ After cessation of treatment: to asses the time taken for drug to be eliminated from the body (in 4-5 half-lifes)

Elimination of a drug during 5 half-lifes of initial level % of total elimination

REPEATED ADMINISTRATION OF DRUGS TIME TO STEADY STATE (attained after 4-5 half-lifes) independen of dose FLUCTUATIONS proportional to dose intervals blunted by slow absorption STEADY-STATE LEVELS (CONCENTRATIONS) proportional to dose t1/2

Steady-state concentrations are proportional to dose Linear kinetics - diazepam toxic plasma concentrations daily therapeutic daily daily Time (days)

Non-linear, saturation kinetics - phenytoin plasma concentrations toxic daily daily therapeutic daily Time (days)

REPEATED ADMINISTRATION OF DRUGS TIME TO STEADY STATE (attained after 4-5 half-lifes) independen of dose FLUCTUATIONS proportional to dose intervals blunted by slow absorption STEADY-STATE LEVELS (CONCENTRATIONS) proportional to dose t1/2

How to reduce fluctuations in drug concentrations? by administering drugs slowly, continually, e.g.: slow i.v. injection, infusion, sustained–release (SR) tablets, slow release from depots (e.g. from patches transdermally, depot antipsychotics injected i.m.) or by administering a total dose (e.g. a daily dose) in parts at shorter intervals (mostly inconvenient)

4. PLASMA CONCENTRATION - EFFECT RELATIONSHIP Effects of drug correlate with plasma concentrations Therapeutic Drug Monitoring (TDM) (eg. gentamicin, lithium, some antiepileptics) do not correlate with plasma concentrations „hit and run“ tolerance or sensitisation active metabolites

The End

Administration of parts of total dose at short intervals produces smaller fluctuations of drug concentrations (levels) an omission of a particular dose* does not need to cause an undesirable fall in drug concentrations (levels) *noncompliance

ABSORPTION Depends on: lipid solubility ionization (depends on pH) non-ionized (non-polar), local changes in the pH routes of administration per os presystemic elimination FIRST-PASS EFFECT pharmaceutical technology BIOAVAILABILITY, bioequivalence parenteral

FIRST-PASS EFFECT: loss of a drug by a metabolism mostly in the liver that occurs en route from the gut lumen to the systemic circulation e.g. in nitroglycerin, morphine

Clinical consequence of the first-pass effect: limited effect after oral administration great interindividual differences in dosage

BIOAVAILABILITY: the proportion of drug that reaches the systemic circulation It is usually calculated from the AUC (Area Under the Curve)