Principles of pharmacokinetics Prof. Kršiak Department of Pharmacology, Third Faculty of Medicine, Charles University in Prague Cycle II, Subject: General pharmacology Lecture: 8th November :00-9:30, Syllaba Hall, Ruská 87, Prague Charles University in Prague, Third Faculty of Medicine

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 M. Kršiak Department of Pharmacology, Third Faculty of Medicine, Charles University in Prague, 2008

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

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 Depends on:

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, V d of digoxin is about 645 liters for a 70 kg man (i.e. about 9 times bigger than his actual volume) VOLUME OF DISTRIBUTION V d = Amount of drug in body / Concentration of drug in plasma

Clinical importance of volume of distribution: When V d 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.

METABOLIC (biotransformation) 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) CL tot total CL R renal CL H hepatic CL NR nonrenal (= Cl tot - CL R )

Bathtube in a hotel with two holes, no plugs, and a plate indicating Vd= 1000 L, CL = 100 mL/min How would you regulate supply of water (water tap) to fill the bath in order to take a bath soon and for a longer time? Example – analogy for utilization of information on volume of distribution (Vd) and clearance (CL):

the half-life is the time taken for the plasma concentration to fall by half [plasmatic half-life]

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

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

Elimination processes are saturated e.g. in alcohol, after higher doses of phenytoin, theophyllin [unstable t 1/2 ] Non-linear (Zero-order, saturation) kinetics 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 The rate of elimination is constant

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

T 1/2 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)

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

T 1/2 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) THE USES OF THE HALF-LIFE

„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 t 1/2 Plasma concentration

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

T 1/2 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) THE USES OF THE HALF-LIFE

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

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 t 1/2 REPEATED ADMINISTRATION OF DRUGS

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

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

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 t 1/2 REPEATED ADMINISTRATION OF DRUGS

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.) by administering a total dose (e.g. a daily dose) in parts at shorter intervals (mostly inconvenient) or

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