Topic 6 Pharmacokinetics andDrug Metabolism

Chapter 8 Patrick

Drug candidate pharmaceutics are critical:ADME

• Absorption• Distribution• Metabolism• Excretion

Drug candidate pharmaceutics are critical:Drug Administration route-

1. Oral

2. Mucous membranes1. Rectal2. Oral (buccal)

3. Topical-transdermal4. Inhaled5. Injected

1. Intravenous2. Intramuscular3. Subcutaneous4. Intrathecal-spinal5. Intraperotoneal

Drug candidate pharmaceutics are critical:Formulations

1. Pills, capsules2. Liquid3. Patch4. Liposome/micelle

Pharmaceutics

TherapeuticWindow mustbe maintainedby dosing

TherapeuticWindow mustbe maintainedby dosing

Pharmaceutics

AbsorptionDrug Absorption, Metabolism and Excretionhttp://www.cc.nih.gov/training/training/principles/schedule.html

1. Acid-base properties

2. Hydrophobicity/Functional groups

3. Size

Drug molecule factors affecting absorption anddistribution

Lipinski’s rules for lousy drug absorption:1. MW>5002. H-bond donors>53. H-bond acceptors>104. log Partition coefficient > 5

i.e. octanol /water > 100,000:1

Absorption

A “good” drug

A “lousy” drug: insulin

Distribution:Serum Albumin, Thedistributor of non polar drugs

Seeing distribution: e.g.fluconazole

PET scan of 18F fluconazole

Metabolism/excretionOxidationPhase I Metabolism

Metabolism/excretion1. Phase 1 metabolism- Liver microsomal system

Metabolism/excretion1. Phase 1 metabolism- Liver microsomal system

Metabolism/excretion

Metabolism/excretion

Metabolism/excretion1. Phase 1 metabolism- Liver microsomal system

Metabolism/excretion1. Phase 1 metabolism

Metabolism/excretion1. Phase 1 metabolism

Metabolism/excretion

EXAMPLE: a Ca 2+ channel blocker for hypertension

EXAMPLE: a Ca 2+ channel blocker for hypertension

Phase II Metabolism

Metabolism/excretionConjugation examples