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Learning objectives • To know what data is available from pharmacokinetic studies in man and how to handle it • To know how to calculate the basic pharmacokinetic parameters of clearance, t(half); volume of distribution, bioavailability; Kel • To understand the implications of these parameters for satisfactory therapy and the construction of suitable dosage regimens for patients • To know how knowledge of pharmacokinetic parameters can be exploited in drug design and formulation development. Pharmacokinetics • Study of ADME on a quantitative basis In man study blood, urine, faeces, expired air. Measure urine volume & concentration of drug conc in urine x vol per min = RENAL plasma concentration CLEARANCE If neither secreted nor reabsorbed then clearance = clearance of inulin = 120 ml/min If completely cleared by secretion then clearance = clearance of p-hippuric acid = renal blood flow = 700 ml/min Plasma concentration 14 Ct = Co e-tKel lnCt = lnCo - Kel t 12 10 logCt = logCo - Kel . t 2.303 8 6 y 4 = c m x 2 0 0 5 10 TIME (hours) 15 20 Bioavailability Plasma concentration 60 i.v. route 50 (AUC)o / (AUC)iv 40 30 oral route 20 Time (hours) 10 0 0 2 4 6 8 =1.5; antilog 1.5 = 31.6 1.6 logCt = logCo - Kel . t 2.303 1.1 0.6 TIME (hours) 0.1 0 5 -0.4 -0.9 log plasma concentration 10 15 20 Pharmacokinetic parameters • Volume of distribution V = DOSE / Co • Plasma clearance Cl = Kel .V • plasma half-life (t1/2) or directly from graph t1/2 = 0.693 / Kel • Bioavailability (AUC)x / (AUC)iv Multiple dosing • On multiple dosing plasma concentration will rise and fall with each dose andwill increase until administration = elimination ie. steady state is reached. • At steady state hourly dose rate (D=dose; T=interval between doses in hours) D/T = clearance x plasma conc or steady state conc = D/(T x clearance) • At each dose the level will oscillate through D/V plasma conc toxic 6 5 4 effective Cumulation and use of loading doses 3 2 1 Time 0 0 5 10 15 20 25