Lecture 12 INTEGRATION OF KINETIC AND PHYSIOLOGICAL CONCEPTS

Lecture #12 INTEGRATION OF KINETIC AND PHYSIOLOGICAL CONCEPTS

Clearance vs. V vs. t 1/2 Increase V; Increase CL Decrease t 1/2; Increase CL Represented Mathematically:

k, t 1/2 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 flow and partitioning – Dose, V, 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, Extraction Ratio (E) 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 Cytochrome P 450 3 A 4

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

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

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

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

high EH (Insensitive to Enzyme Activity) Heart Drug P 450 Inducer Pentobarbital Inhibitors? Cytochrome P 450 (P 450)

high EH (Insensitive to Enzyme Activity) Recall: Low Inhibition P 450 Inhibitor P 450 = Cytochrome P 450 Inhibitor synthetic opioid analgesic

high EH (Insensitive to Enzyme Activity) High Inhibition P 450 inhibitor P 450 = Cytochrome P 450 synthetic opioid analgesic

High EH (Insensitive to Enzyme Activity) d ibit e Inh ed ibit Hepatic Extraction Ratio (EH) Inh Hepatic Clearance (CLH) CLint =1000 L/hr fu = 1 Induced

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

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

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

high EH (Insensitive to k and t 1/2) Elim. Rate Constant (k) Half time (t 1/2) CLint =1000 L/hr

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 t 1/2 • High Eh – Insensitive to enzyme activity/concentration (CLint) – Sensitive to hepatic blood flow (Qh) – Insensitive to protein binding (fu) – Insensitive to k and t 1/2

a b

Excretion Rate

fu vs. Renal Excretion Rate R n tio a Tot S tra l Fil tion e r ec ate R n tio a r t l Fi ate Glome ion R t a r t l i F s rulu

fu vs. Renal Clearance diuretic

T l ota Excretion Rate in mg/hr units n tio e r c Se Filtration Renal Extraction Rate (mg/hr) Renal Clearance (L/hr) Clearance in L/hr units al Tot n tio e r c Se Filtration

Relationship of ER and CLR

Rates vs. Clearance Increases with Cu Constant Increases with Cu

ER is variable Renal Extraction Ratio Excretion Rate r) e Tot e xcr E l a tio at n. R Sec r n etio e Rat Filtration Rate /h (mg/hr)

EH is essentially constant for high EH drugs Cannot change blood flow that much. Otherwise, you kill the patient. EH is variable for low EH drugs

Relationships