MS STUDENTS: QUESTIONS TO KNOW SECTION

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PROCESSES OF ELIMINATION AND CLEARANCE Lecture #9

CYP = Cytochrome P450 UDPG = UDP glucuronosyltransferase

Pathways of Drug Metabolism Oxidation and Reduction Conjugation Drugs 5

Phase I versus Phase II? 6 A B C D

Functions Good – Drug Clearance – Toxin Removal* – Homeostasis and Regulation* – Prodrug (inactive)  Active Drug* Bad -Reduced Efficacy -Increased Toxicity* 7

Functions: Toxin Removal bisphenol A Sulfonation Glucuronidation 8

Functions: Homeostasis and Regulation 9

Functions: Prodrug  Drug Antidepressant Antihistamine (Fura et al., 2004) Antihistamine Analgesic 10

Functions: Increased Toxicity Toxic Pathway 11

Abundance Contributions

Elimination Rate Example Midazolam: Dose = 7.5 mg CL = 28 L/hr V = 140 L C V =A/V = 7.5 mg/140 L = 0.05 mg/L Rate of Elimination (mg/hr) = 28 L/hr * 0.05 mg/L = 1.4 mg/hr

Extraction Rate and Extraction Ratio

=1 =E Extraction Rate Units = mg/hr

Fraction Remaining Q* Extraction Ratio Units = Unitless

Clearance Units= L/hr

Clearance Kidneys Liver Blood Flow (Q) Q H =Q R =1 L/hr/kg Q H =Q R =70 L/hr

Clearance Organ – Hepatic (liver) – Renal (kidneys) – Pulmonary (lungs) Process – renal/extrarenal – metabolic and excretory clearance Site of Measurement – reference fluid (blood vs. plasma clearance)

Additivity of Clearance Rate of Elimination Rate of Renal Excretion Rate of Hepatic Metabolism Rate of Biliary Excretion Rate of Other = % 6%69% <1% Not Shown On Pie Chart CYP = cytochrome P450 UDP = UDP glucuronsyltransferases

Additivity of Clearance Rate of Elimination Rate of Renal Excretion Rate of Hepatic Metabolism Rate of Biliary Excretion Rate of Other = % 6%69% <1%

Additivity of Clearance Rate of Elimination Rate of Renal Excretion Rate of Hepatic Metabolism Rate of Biliary Excretion Rate of Other = % 6%69% <1% CVCV CVCV CVCV CVCV CVCV ~6%

Elimination Rate System Circulation Elimination rate CVCV CuCu C blood Assumption: Rapid equilibria between blood, plasma, bound and unbound.

Plasma versus Blood Clearance Binding of drugs to drug-binding proteins in the plasma. Binding to blood cells extensive. = 0.3 to 2.0

Plasma versus Blood Clearance DrugC V, µMC blood, µMC V /C blood Indomethacin Loperamide Moxalaction DrugC V /C blood Amytriptyline1.13 Imipramine1.17 Nortriptyline1.67 Maprotiline2.23 Nomifensine1.21 Diazepam0.71

Plasma versus Blood Clearance Example Verapamil: Plasma/Blood ratio = 1.29 CL = 9 L/hr/kg V = 4.3 L/kg A = mg/kg CL = 630 L/hr V= 301 L A= 10 mg Calculate C V C V =A/V=10 mg/301 L = mg/L Calculate C blood Plasma/Blood ratio=1.29=(0.033 mg/L)/C blood C blood = mg/L Calculate CL blood CL blood =CL*(C V /C blood ) CL blood =630 * 1.29 CL blood = L/hr

Total (CL) versus Unbound Clearance (CL U ) CL = 0.26 L/hr/kg CL = 18.2 L/hr (70 kg) f u = (i.e. ~95% bound) CL U =18.2/0.048 CL U =379 L/hr! tyrosine kinase inhibitor (anti-cancer)