PHARMACOKINETICS •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 • • • absorption A distribution D metabolism M excretion E - processes of ADME • • •“ADME“ •elimination • •invasion Pharmacokinetics 05 •Administration of drug •Absorption •free •drug •free •drug •free •drug •drug bound to proteins or blood cells •metabolite •bound to protein •or blood cell •metabolite •receptor •receptor •free •metabolite •free •metabolite •Biotransformation •organs •depot •binding •depot •binding •TISSUES •BLOOD CIRCULATION •ORGANS OF •EXCRETION •EXCRETION 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 •Stomach pH 1-2 •Parietal cell+ vascular endothelial cell •pH 7.2-7.4 •AH >>> H++A- •BH+ >>> B + H+ • •AH <<< A- + H+ •BH+ <<< B + H+ http://icp.org.nz/icp_t11.html 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) • obrazek lepsi2 •Time •Concentration of drug Bioavailability- F http://icp.org.nz/icp_t6.html http://icp.org.nz/icp_t6.html SET = systemic enzymotherapy AUC – area under the curve 1 • •Effects of different bioavailability (F) on the pharmacokinetics 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 •David G. Bailey, and George K. Dresser CMAJ 2004;170:1531-1532 •P-glycoprotein – –transmembrane pump encoded by MDR1, ABCB1 –drug efflux pump for xenobiotics –multidrug resistence to chemotherapeutics • – http://icp.org.nz/icp_t15.html?htmlCond=3 •Presystemic elimination •First pass effect intupta http://icp.org.nz/icp_t6.html?htmlCond=1 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 • •T [min] •s.c. •p.o. •i.m. •i.v. •c 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 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 •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. Distribution •Distribution volume - use: •Calculation of initial dose: •D = Vd . cT • • • 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 • 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 • Vysvětleno na přednášce, lze se zeptat. •0 and 1st.-order elimination • •time •1 2 3 4 5 •10 •8 •6 •4 •2 • • • • • • • • • • •conc. •time •1 2 3 4 5 •10 •8 •6 •4 •2 •5 •2.5 •1.25 •2 •2 •2 non-linear linear http://icp.org.nz/icp_t9.html?htmlCond=1 http://icp.org.nz/icp_t9.html?htmlCond=1 • • Biotransformation - metabolism •Predominantly in liver, but also in other organs and parts of body • •Enzymatic processes •bioactivation (prodrug) • tamoxifen – endoxifen • cyclophosphamide – phosphoramide •biodegradation • 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 • Biotransformation - metabolism bacter mollusc evolution •human •plants •insect •fungus •yeasts •bacteria •molluscous •animals yeast anopheles CYP 450 dictyostelium3 grizzly-big • CYP 2D6 30% CYP 1A2 2% CYP 2C9 10% ostatní 3% CYP 3A4 55% • • CYP 3A4 • CYP 2D6 • CYP 2C9 • CYP 1A2 • others others •Inducers of CYP450 •dexametazon •fenobarbital •rifampicine •fenytoin •St. John´s worth (Hypericum perforatum) •Maidenhair Tree (Ginkgo biloba) • •Inhibitors of CYP450 •antidepressants (fluoxetin, fluvoxamin, paroxetin) •chinin, chinidin •chloramphenicol, erytromycine •ketokonazol, itrakonazol •grapefruit juice • Excretion •kidneys •bile •lungs • •Saliva, skin, hair, milk… • • • 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 • • 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 • • •Glomerular capillary •Proximal tubulus •H++A- ↔ HA •B ++OH- ↔ BOH •pH < 7 •pH > 7 •H++A- → HA •HA → H++A- •B++OH- → • BOH •BOH → B++OH- http://icp.org.nz/icp_t11.html Pharmacokinetic parameters Mathematic description of pharmacokinetic processes and its use in drug dosage opakovane1 •The guide for evaluation of pharmacokinetics in clinical practise is plasma concentration/time curve – problems with measuring in vivo 1 •In accordance with concentration-time curves we determine pharmacokinetic parameters – model values, which proviídes 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 Single dose •Invasion phase • •C max • •T max • •Bioavailability - F • • • •Volume of distribution - Vd • • • •Relationship of plasmatic conc. on time •Tmax •lag time •Cminter •Cmaxter •T [min] • •THERAPEUTICAL RANGE •INVASION ELIMINATION 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] • ELIMINACE léčiva můžeme popsat těmito parametry: Pro kinetiku 1. řádu platí: Udává pokles koncentrace za určitý čas. fU - fraction unchanged fU = U / D = CLREN /CLTOT Amount of unchanged drug found in urine fU paracetamol = 3% fU gentamycine = 98% polocas1 •ct = c0 . e(-k.t) •ln ct = lnc0 - ke.t •First-order kinetics – semilogaritmic plot (i.v.) • • • • • •ln (c) •time •1 2 3 4 5 • • • •time •1 2 3 4 5 •10 •8 •6 •4 •2 • • • • • •5 •2.5 •1.25 •ln ct = lnc0 - ke.t •y = -ke . x +b •ct = c0 . e(-k.t) •c •10 •8 •6 •4 •2 • Compartment models Compartment = space, where is drug equally distributed •i.v. intake •Compartment models– block schema •1- compartment model • • •Vd •ke • • •A (GIT) •ka •D • • • •Vd •D •ke • • • •i.v. intake •Vd1 •k10 • • • •Vd2 •k12 •k21 •central compartment •peripheral compartment •D • •Compartment models– block schema •2- compartment model opakovane1 •Continuous and repeated administration of drugs • •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) •Continuous administration •Continuous administration •minimal toxic concentration •Time •minimal therapeutic concentration •patient A – clearence = 100ml/min •patient B – clearence = 50ml/min •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 infuze2 •Continuous administration End of i.v. infusion Time (in biological halftimes) •intra- (repeated intravascular injection) or extravascular (i.e. per os) • rychlost přívodu [mg/min] = Cl x Css • •Repeated administration •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 •Repeated administration •cmax = maximal plasmatic concentration •tmax = time when cmax is reached •ka = absorption rate constant •ke = elimination rate constant • • t1/2 = biological halftime • • •Vd = volume of distribution • • •Cl = clearance • • • • • • •AUC = area under the curve • Basic pharmacokinetic parameters (+computations)