Adobe Systems Department of Pharmacology 1 PHARMACOKINETICS Notes for Students This study material is exclusively for students of general medicine and stomatology in Pharmacology I course. It contains only basic notes of discussed topics, which should be completed with more details and actual information during practical courses to make a complete material for test or exam studies. Which means that without your own notes from the lesson this presentation IS NOT SUFFICIENT for proper preparation for neither tests in practicals nor the final exam. Adobe Systems Basic principles of pharmacokinetics Pharmacokinetics is aimed on this processes: absorption distribution biotransformation excretion of drugs and their relation to pharmacologic (therapeutic or toxic) effects Adobe Systems Pharmacokinetics absorption A distribution D metabolism M excretion E - processes of ADME “ADME“ elimination invasion Adobe Systems 05 Administration of drug Absorption depot binding receptor free drug free drug free drug Biotransformation organs drug bound to proteins or blood cells receptor depot binding metabolite free metabolite metabolite bound to protein or blood cell free metabolite TISSUES BLOOD CIRCULATION ORGANS OF EXCRETION EXCRETION Adobe Systems General rules for drug movement 1.Physical-chemical characteristic of drug lipophilic vs hydrophilic, size, charge, pKa, solubility 2.Drug transmission through biological barriers lipophilic - pasive diffusion hydrophilic- pore transmission active transport vesicular transport – pinocytosis, phagocytosis 3.Drug binding plasmatic proteins blood cells tissue binding receptor binding 4.Tissue perfusion a)brain, heart, liver and kidney b)adipose tissue http://icp.org.nz/icp_t11.html Adobe Systems Absorption – routes of administration ̶penetration of dissolved drug from the site of administration to blood (systemic circulation) – necessary for general effect– systemic effect ̶Local effect: ̶on skin, mucosas or ventricles ̶absorption is undesirable – possible AE ̶ie. local corticoids, local anesthetics Speed and extent of absorption are described by P-kinetic parameters: C max max. concentration of drug in plasma after single dose T max time, when drug reach cmax (speed) F bioavailability (extent) ̶ Adobe Systems obrazek lepsi2 Concentration of drug Time Adobe Systems Bioavailability- F http://icp.org.nz/icp_t6.html Adobe Systems AUC – area under the curve 1 Adobe Systems Bioavailability- F ̶Absolute bioavailability ̶comparing the AUC of administered drug in the test dosage form and the AUC after i.v. drug administration ̶ ̶Relative bioavailability ̶assess the expected biological equivalence of two preparations of a drug ̶if the relative bioavailability = 1 (100%) à tested preparation is bioequivalent to the reference Adobe Systems David G. Bailey, and George K. Dresser CMAJ 2004;170:1531-1532 Adobe Systems P-glycoprotein – –transmembrane pump encoded by MDR1, ABCB1 –drug efflux pump for xenobiotics –multidrug resistence to chemotherapeutics – Adobe Systems Presystemic elimination First pass effect intupta http://icp.org.nz/icp_t6.html?htmlCond=1 Adobe Systems Other factors influencing drug absorption ̶gender, weight, plasmatic volume, speed of gastric discharging ̶age - pH, bile, enzymes ̶pathophysiological defect – diseases of liver, inflammation ... ̶body constitution (BW/LBM) ̶diet - acceleration/ decceleration - chemical incompatibilities - GIT functionality ̶ Adobe Systems T [min] s.c. p.o. i.m. i.v. c Adobe Systems Distribution ̶Penetration of drug from blood to tissues, dynamic proces where we are interested in: speed of distribution- depends on: bindings membrane penetration organ perfusion status- distribution balance, free fractions of drug are equal in blood and tissue Volume of distributionVd ̶hypothetic, theoretical volume ̶rate between amount of drug in organism and plastmatic concentration ̶ http://icp.org.nz/icp_t3.html?htmlCond=0 Adobe Systems The apparent volume of distribution, Vd, is defined as the volume that would contain the total body content of the drug at a concentration equal to that present in the plasma Adobe Systems Adobe Systems Adobe Systems Vd = hypothetical volume, Final value of Vd can be even 50000 liters (antimalarial drugs). What does this value tell us: We can assess distribution of the drug in the body. Adobe Systems Distribution Distribution volume - use: Calculation of initial dose: D = Vd . cT Adobe Systems Distribution Estimate the amount of drug in the body M = Vd . C Assessment of the effect of hemodialysis and hemoperfusion ̶drugs with higher Vd can not be eliminate from the body by these technics Adobe Systems Elimination of drugs First-order elimination ̶Elimination speed is influenced by plasmatic concentration ̶Linear kinetics ̶ Zero-order elimination ̶Elimination speed is not influenced by plasmatic concentration ̶Non-linear kinetics Adobe Systems Biotransformation - metabolism ̶Predominantly in liver, but also in other organs and parts of body Enzymatic processes ̶bioactivation (prodrug) tamoxifen – endoxifen cyclophosphamide – phosphoramide ̶biodegradation ̶ Adobe Systems Biotransformation - metabolism 1.Phase: ̶oxidation, hydrolysis à drug is still partly lipophilic ̶cytochromes P450, dehydrogenases 2.Phase: ̶conjugation à molecules becomes hydrophilic Metabolites - effective („more/less“) - inneffective - toxic ̶ Adobe Systems CYP 450 Adobe Systems CYP 2D6 30% CYP 1A2 2% CYP 2C9 10% ostatní 3% CYP 3A4 55% CYP 3A4 CYP 2D6 CYP 2C9 CYP 1A2 others Adobe Systems Inducers of CYP450 •dexametazon •fenobarbital •rifampicine •fenytoin •St. John´s worth (Hypericum perforatum) •Maidenhair Tree (Ginkgo biloba) • Adobe Systems Inhibitors of CYP450 •antidepressants (fluoxetin, fluvoxamin, paroxetin) •chinin, chinidin •chloramphenicol, erytromycine •ketokonazol, itrakonazol •grapefruit juice • Adobe Systems Excretion kidneys bile lungs Saliva, skin, hair, milk… ̶ Adobe Systems Excretion by kidney ̶MW < 60.000 D (MW of albumin = 68.000 D) ̶glomerular filtration ̶tubular secretion ̶organic acids furosemide thiazide diuretics penicilins glukuronids ̶organic bases morfin ̶tubular reabsorption diazepam ̶ alkalization natrium hydrogencarbonate acidification ammonium chloride Adobe Systems Excretion by liver ̶Substances permeate through 2 membranes of hepatocytes – basolateral and apical (canalicular) ̶Metabolites are excreted primary by pasive diffusion, further by active transport (glucuronides, bile acids, penicillins, tetracyclines, etc.) ̶Metabolites can be deconjugated by bacterial enzymes in intestine à release of lipophilic molecule à re-absorption = ENTEROHEPATIC CIRCULATION Adobe Systems polocas1 Adobe Systems Pharmacokinetic parameters Mathematic description of pharmacokinetic processes and its use in drug dosage Adobe Systems The guide for evaluation of pharmacokinetics in clinical practise is plasma concentration/time curve – problems with measuring in vivo 1 opakovane1 Adobe Systems •In accordance with concentration-time curves we determine pharmacokinetic parameters – model values, which provides us to describe P-kinetic processes •There are three possible manners of drug administration with regards to concentration-time curves: single dose continuous administration repeated dose Adobe Systems Single dose Invasion phase C max T max Bioavailability - F Volume of distribution - Vd ̶ Adobe Systems Relationship of plasmatic conc. on time Cmaxter THERAPEUTICAL RANGE Tmax lag time T [min] INVASION ELIMINATION Cminter Adobe Systems Single dose Elimination phase ̶Drug is eliminated from the organism with speed determined by: Elimination rate constant: Biological halftime – drug is totally eliminated after 4-5 halftimes Clearance = volume of plasma, which is fully cleaned from drug at time unit[l . h-1] Adobe Systems Compartment models Adobe Systems Compartment models– block schema 1- compartment model Vd D ke i.v. intake Vd ke A (GIT) ka D Adobe Systems Compartment models– block schema 2- compartment model i.v. intake Vd1 k10 Vd2 k12 k21 central compartment peripheral compartment D Adobe Systems Continuous and repeated administration of drugs opakovane1 Adobe Systems Continuous administration •Intravenous (e.g. by infusio pump), transdermal (TTS), implant à administration of drug with constant speed (mg/min) • •If duration of infusion is long enought, concentrations are increasing until the speed of elimination and inflow are the same – plato state is reached (concentration of plato is expressed as Css) Adobe Systems minimal toxic concentration Time minimal therapeutic concentration patient A – clearence = 100ml/min patient B – clearence = 50ml/min Continuous administration Adobe Systems In plato: •Drug is binded to all binding sites, which can be occupied (distribution is finished) •constant infusion speed supplements amount, which is eliminated from organism in same •speed of inflow [mg/min] = speed of elimination [mg/min] Continuous administration Adobe Systems infuze2 End of i.v. infusion Time (in biological halftimes) Continuous administration Adobe Systems Repeated administration intra- (repeated intravascular injection) or extravascular (i.e. per os) Adobe Systems •If doses are administered so close that first of them is not fully eliminated, cumulation starts or plato is reached •Instead of css, cssplato is described and it is an average concentration from all concentrations meaured during one dosage interval Repeated administration Adobe Systems Repeated administration Adobe Systems Basic pharmacokinetic parameters (+computations) cmax = maximal plasmatic concentration tmax = time when cmax is reached ke = elimination rate constant t1/2 = biological halftime Vd = volume of distribution Cl = clearence AUC = area under the curve