Adobe Systems PHARMACOKINETICS Jan Juřica, PharmD. Ph.D. General principles of the fate of the drug in the body Overview of pharmacokinetic processess: Drug absorption, distribution, metabolism and excretion [USEMAP] 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 [USEMAP] absorption A distribution D metabolism M excretion E - processes of ADME “ADME“ elimination invasion Pharmacokinetics [USEMAP] 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 [USEMAP] Concentr. in the blood Conc. at the site of action (biophase) Drug effect [USEMAP] General features of drug movement across the body 1.Physical-chemical characteristic of drug lipophilic vs hydrophilic, MW, 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 4.Tissue perfusion brain, heart, liver and kidney adipose tissue [USEMAP] 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 [USEMAP] 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) [USEMAP] [USEMAP] obrazek lepsi2 Time Concentration of drug [USEMAP] Bioavailability- F http://icp.org.nz/icp_t6.html [USEMAP] http://icp.org.nz/icp_t6.html SET = systemic enzymotherapy AUC – area under the curve 1 [USEMAP] Effects of different bioavailability (F) on the pharmacokinetics [USEMAP] 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 [USEMAP] David G. Bailey, and George K. Dresser CMAJ 2004;170:1531-1532 [USEMAP] P-glycoprotein – –transmembrane pump encoded by MDR1, ABCB1 –drug efflux pump for xenobiotics –multidrug resistence to chemotherapeutics – [USEMAP] http://icp.org.nz/icp_t15.html?htmlCond=3 Presystemic elimination First pass effect intupta http://icp.org.nz/icp_t6.html?htmlCond=1 [USEMAP] 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 [USEMAP] T [min] s.c. p.o. i.m. i.v. c [USEMAP] 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 [USEMAP] 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 [USEMAP] [USEMAP] [USEMAP] 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. [USEMAP] Distribution Distribution volume - use: Calculation of loading dose: D = Vd . cT [USEMAP] 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 techniques [USEMAP] Elimination of drugs First-order elimionation Rate of elimination is influenced by plasmatic concentration Linear kinetics Zero-order elimination Elimination rate is not influenced by plasmatic concentration Non-linear kinetics [USEMAP] Vysvětleno na přednášce, lze se zeptat. 0 and 1st.-order elimination non-linear linear ln (c) time 1 2 3 4 5 time 1 2 3 4 5 10 8 6 4 2 5 2.5 1.25 c 10 8 6 4 2 [USEMAP] 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 [USEMAP] 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 [USEMAP] bacter mollusc evolution human plants insect fungus yeasts bacteria molluscous animals yeast anopheles CYP 450 dictyostelium3 grizzly-big [USEMAP] CYP 2D6 30% CYP 1A2 2% CYP 2C9 10% ostatní 3% CYP 3A4 55% CYP 3A4 CYP 2D6 CYP 2C9 CYP 1A2 others others [USEMAP] Inducers of CYP450 •dexametazon •fenobarbital •rifampicine •phenytoin •St. John´s worth (Hypericum perforatum) •Ginkgo biloba • [USEMAP] Inhibitors of CYP450 •antidepressants (fluoxetin, fluvoxamin, paroxetin) •chinin, chinidin •chloramphenicol, erytromycine •ketokonazol, itrakonazol •grapefruit juice • [USEMAP] Genetic polymorfism of CYP 450 [USEMAP] [USEMAP] Excretion kidneys bile lungs Saliva, skin, hair, milk… [USEMAP] 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 [USEMAP] 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 [USEMAP] 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 [USEMAP] Adobe Systems Pharmacokinetic parameters Mathematic description of pharmacokinetic processes and its use in drug dosage [USEMAP] opakovane1 The guide for evaluation of pharmacokinetics in clinical practise is plasma concentration/time curve – problems with measuring in vivo 1 [USEMAP] •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 [USEMAP] Single dose Invasion phase C max T max Bioavailability - F Volume of distribution - Vd [USEMAP] Relationship of plasmatic conc. on time Tmax lag time Cminter Cmaxter T [min] THERAPEUTIC RANGE INVASION ELIMINATION [USEMAP] Single dose Elimination phase Drug is eliminated from the organism with speed determined by: Elimination rate constant: Biological halflife – drug is totally eliminated after 4-5 halflifes Clearance = volume of plasma, which is fully cleaned from drug at time unit[l . h-1] [USEMAP] 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 gentamicine = 98% polocas1 ct = c0 . e(-k.t) ln ct = lnc0 - ke.t [USEMAP] 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 [USEMAP] Adobe Systems scan 4 [USEMAP] Adobe Systems Compartment models [USEMAP] 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 [USEMAP] i.v. inflow Vd1 k10 Vd2 k12 k21 central compartment peripheral compartment D Compartment models– block schema 2- compartment model [USEMAP] opakovane1 Continuous and repeated administration of drugs [USEMAP] •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 [USEMAP] Continuous administration minimal toxic concentration Time minimal therapeutic concentration patient A – clearence = 100ml/min patient B – clearence = 50ml/min [USEMAP] In plato: •Drug is binded to all binding sites, which can be occupied •constant infusion rate supplements amount, which is eliminated from organism in same time frame •rate of drug administration [mg/min] = rate of elimination [mg/min] Continuous administration [USEMAP] infuze2 Continuous administration End of i.v. infusion Time (in biological halflifes) [USEMAP] •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 [USEMAP] intra- (repeated intravascular injection) or extravascular (i.e. per os) rychlost přívodu [mg/min] = Cl x Css Repeated administration [USEMAP] cmax = maximal plasmatic concentration tmax = time when cmax is reached ka = absorption rate constant ke = elimination rate constant t1/2 = biological halflife Vd = volume of distribution Cl = clearance AUC = area under the curve Basic pharmacokinetic parameters (+ computations) [USEMAP]