Lecture 13 review nephron structure significance to lipid

Lecture 13 review: nephron structure – significance to lipid soluble drugs? (cortex) (medulla)

Enterohepatic circulation Figure 43 -13 of RM Berne, MN Levy “Physiology” 1983, Mosby

Will imatinib last forever in the body? P=24, 000

Lecture 14: Drug biotransformation (Chapter 8 of Levine’s Pharmacology) Important definitions: 1. biotransformation vs metabolism 1. xenobiotics Q 1: Why do we have enzymes that metabolize/ biotransform drugs? What is the evolutionary rationale for their presence?

FIRST PASS METABOLISM slideplayer. com

Hepatic blood flow slideplayer. com

Tissue distribution of drug biotransforming activity Figure 13 -1 of CR Craig and RE Stitzel “Modern Pharmacology with Clinical Applications” fifth edition 1997, Little Brown

Q: What does an organic chemist look for in evaluating the potential reactivity of a molecule?

Q: What does an organic chemist look for in evaluating the potential reactivity of a molecule?

Q: What does an organic chemist look for in evaluating the potential reactivity of a molecule?

Phase I reactions- Cytochrome P 450 monooxygenases www. agnet. org/library/ image/tb 159 f 1. html

Example oxidative reactions Table 1 -2 of JG Hardman, LE Limbird, PB Molinoff, RW Ruddon and AG Gilman “Pharmacological Basis of Therapeutics” 1996, Mc. Graw-Hill.

Primary CYP 2 E 1 metabolites of imatinib

Fraction of drugs metabolized by different cytochrome P 450 enzymes Figure 1 -4 of JG Hardman, LE Limbird, PB Molinoff, RW Ruddon and AG Gilman “Pharmacological Basis of Therapeutics” 1996, Mc. Graw-Hill.

Reasons for Attrition (Lecture 8) Kola and Landis (2004). Nature Rev. Drug Disc. 3: 711 -715.

Genetic Polymorphisms within the cytochrome P 450 genes

Q: What could happen if two different drugs were administered that are acted upon by the same CYP 450 enzyme?

Competition can be lethal Seldane (prodrug) Important definition: prodrug Allegra (active metabolite)

A prodrug designed to exploit a biotransformation reaction so as to bypass a pharmacokinetic limitation levodopamine Figure 33. 2 of CR Craig and RE Stitzel “Modern Pharmacology with Clinical Applications” fifth edition 1997, Little Brown

Cytochrome P 450 properties Table 3. 3 of CR Craig and RE Stitzel “Modern Pharmacology with Clinical Applications” fifth edition 1997, Little Brown

Cytochrome P 450 Figure 3. 3 of CR Craig and RE Stitzel “Modern Pharmacology with Clinical Applications” fifth edition 1997, Little Brown

Cytochrome P 450 induction http: //herkules. oulu. fi/isbn 9514258649/html/graphic 22. png

Toxic metabolites can be created by cytochrome P 450 biotransformations Drug Metabolism and Disposition 31; 1499 -1506, 2003

More Phase I reactions: hydrolysis Table 1 -2 of JG Hardman, LE Limbird, PB Molinoff, RW Ruddon and AG Gilman “Pharmacological Basis of Therapeutics” 1996, Mc. Graw-Hill.

Phase II reactions - glucuronidation Table 1 -2 of JG Hardman, LE Limbird, PB Molinoff, RW Ruddon and AG Gilman “Pharmacological Basis of Therapeutics” 1996, Mc. Graw-Hill.

Additional Phase II reactions 1. amino acid conjugation Page 159 of RL Levine “Pharmacology Drug Actions and Reactions” sixth edition 2000, Parthenon Publishing Ø The amino acid glutamine is also often used in conjugation reactions as well. 2. sulphate conjugation 3. acetate conjugation

Acetaminophen inactivation Drug Metabolism and Disposition 31; 1499 -1506, 2003

Biotransformation rxns: summary

Primary metabolites of aspirin Figure 4 -11 of TM Brody, J Larner and KP Minneman “Human Pharmacology, Molecular to Clinical” 1998, Mosby.