MS Phoenix WinNonLin Project Due 9/21/15 Non-compartment analysis (NCA) of simulated oral plasma data Everyone uses drug. Plot and Table

Integration of Kinetic and Physiological Concepts Lecture #12 Integration  of  Kinetic  and  Physiological   Concepts

Clearance vs. V vs. t1/2 Increase V; Increase CL Decrease t1/2; Increase CL

k, t1/2 and AUC Unspoken Assumption: First Order Exponential Decay Kinetics

Future Current: Kinetics IV bolus dose We will Kinetics Extravascular Dose Constant-Rate Input Multiple-Doses Disease Non-linearities Drug Interactions

PK Parameters vs. Physiological Variables Primary PK Parameters Protein binding, enzyme activity, blood flows and partitioning Dose, V, CL, CLH, CLR, CLINT, dose, fu, blood-to-plasma equilibration ratio, Q, QR, QH Secondary PK Parameters Depend on Primary PK parameters Drug Concentrations, Rate Constants, AUC k = CL/V Observations AUC = Adose/CL CMAX = Adose/V Cu = fu (Adose/V)

Hepatic Extraction Ratio (EH) High EH Clearance cannot exceed hepatic blood flow (QH) Low EH

Hepatic Extraction Ratio (Eh) Enzymatic Activity/Concentration (CLint) Hepatic Blood Flow (Qh) Protein Binding (fu)

Low EH (Sensitive to Enzyme Activity) Inhibitor opioid analgesic drug Inducer Rifpampin http://www.ncbi.nlm.nih.gov/pubmed/17381666 https://en.wikipedia.org/wiki/Rifampicin (Antibiotic) Troleandomycin (macrolide antibiotic) https://en.wikipedia.org/wiki/Troleandomycin Cytochrome P450 3A4

Low EH (Sensitive to Enzyme Activity) Inhibited CLint =1 L/hr fu = 1 Hepatic Clearance (CLH) Induced Hepatic Extraction Ratio (EH)

Low EH (Insensitive to hepatic blood flow (QH)) CLint =1 L/hr fu = 1 Hepatic Clearance (CLH) Hepatic Extraction Ratio (EH)

low EH (Sensitive to Protein Binding) CLint =1 L/hr Hepatic Clearance (CLH) Hepatic Extraction Ratio (EH)

low EH (Sensitive to k and t1/2) CLint =1 L/hr Elim. Rate Constant (k) Half time (t1/2)

high EH (Insensitive to Enzyme Activity) Heart Drug P450 Inducer Pentobarbital is a sedative. https://en.wikipedia.org/wiki/Pentobarbital Pentobarbital Inhibitors? Cytochrome P450 (P450)

high EH (Insensitive to Enzyme Activity) Low Inhibition Recall: P450 Inhibitor P450 Inhibitor Cytochrome P450 3A4 inhibitor P450 = Cytochrome P450 synthetic opioid analgesic

high EH (Insensitive to Enzyme Activity) High Inhibition P450 inhibitor P450 = Cytochrome P450 synthetic opioid analgesic

High EH (Insensitive to Enzyme Activity) Induced Inhibited CLint =1000 L/hr fu = 1 Hepatic Clearance (CLH) Hepatic Extraction Ratio (EH) Induced Inhibited

high EH (Sensitive to Blood Flow) Reduce QH Local Anesthetic Anti-hypertensive Anti-hypertensive

high EH (Sensitive to Blood Flow) CLint =1000 L/hr fu = 1 Hepatic Clearance (CLH) Hepatic Extraction Ratio (EH)

high EH (Insensitive to Protein Binding) CLint =1000 L/hr Hepatic Clearance (CLH) Hepatic Extraction Ratio (EH)

high EH (Insensitive to k and t1/2) CLint =1000 L/hr Elim. Rate Constant (k) Half time (t1/2)

Hepatic Clearance (CLh) Summary Low Eh Sensitive to enzyme activity/concentration (CLint) Insensitive to hepatic blood flow (Qh) Sensitive to protein binding (fu) Sensitive to k and t1/2 High Eh Insensitive to enzyme activity/concentration (CLint) Sensitive to hepatic blood flow (Qh) Insensitive to protein binding (fu) Insensitive to k and t1/2

a b a b

Excretion Rate

fu vs. Renal Excretion Rate Total Filtration Rate Secretion Filtration Rate Glomerulus Filtration Rate

fu vs. “Renal Excretion Rate” Excretion Rate in units of clearance (volume/hour) diuretic

Total Secretion Filtration Excretion Rate in L/hr units Excretion Rate in mg/hr units

Renal Extraction Ratio (ER)

Constant ER Renal Extraction Ratio Excretion Rate Total Excretion Rate Filtration Rate Secretion Rate

Constant EH

Relationships