Principles of

Clinical Pharmacology
 Introduction to Module 3:
Drug Metabolism & Transport

Dr. Lisa M. Cordes, PharmD, BCACP, BCOP

Oncology Clinical Pharmacy Specialist and Educator
National Institutes of Health
 Introduction to
Drug Metabolism and Transport

Dr. Lisa M. Cordes, PharmD, BCACP, BCOP

Oncology Clinical Pharmacy Specialist & Educator
National Institutes of Health
Disclosures
This presentation reflects my views only, not those of the
National Institutes of Health or the US Federal Government
Introductory Lecture
Drug Metabolism Drug Transporters
• Introduction and clinical relevance • Introduction and clinical relevance
• Phase I & Phase II • ABC & SLC superfamilies
• Example: Cytochrome P450 (CYP450) • Example: P-glycoprotein (P-gp)
Basics of Drug Metabolism Absorption

• What is metabolism?
• The biotransformation of a substance into a new entity Distribution
• Primary objective
• To increase the hydrophilicity of lipophilic compounds to Metabolism
allow for elimination

Elimination
• Where does metabolism occur?
• Primarily hepatic enzymes
• Small intestine for oral agents
• Other sites to a lesser extent
 The Clinical Relevance of Drug Metabolism

Active compound Inactive compound

Inactive compound Active compound

Inactive/active compound Toxic metabolite

 Phases of Metabolism
Phase I Phase II
Mechanism Functionalization Conjugation
Converts the parent drug to a more Covalent linkage is formed between
polar metabolite by introducing or a functional group on the parent
unmasking a functional group compound or metabolite and an
(e.g. –OH, -NH2, -SH) endogenous substrate
Types of reactions Oxidation Glucuronide conjugation, sulfate
Hydrolysis conjugation, acetylation, others
Reduction
Primary location Endoplasmic reticulum Cytosol
of action
Change in Minor increase Major increase
hydrophilicity
First-Pass Metabolism
• Impacts oral agents
• Significant metabolic
inactivation in either the
intestinal endothelium
and/or the liver before it
reaches the systemic
circulation
• Therapeutic implications

Image from: Bailey DG et al. CMAJ, March 5, 2013. 185 (4); 309-316
 Cytochrome P-450
What is the CYP450 system? Significance of the CYP450 system
• Microsomal superfamily of enzymes • Phase I metabolism
that catalyzes the oxidation of
xenobiotics • CYP450 enzymes account for 70-
80% of enzymes involved in drug
metabolism
Cyto: bound to membranes within a cell
• Most significant enzymes are
chrome P: contains a heme pigment
CYP3A4 and CYP2D6
450: absorbs light at a wavelength of 450nm
when exposed to carbon monoxide

CYP3A4: CYP, group 3, subgroup A, gene 4

 Factors Influencing Drug Metabolism
• Genetic factors

Poor Intermediate Normal Rapid Ultrarapid

Metabolizers Metabolizers metabolizers Metabolizers Metabolizers

Example:
CYP2D6 substrate administered

↓ metabolism expected metabolism ↑ metabolism

↑ toxicities expected toxicities & efficacy ↓ efficacy
Factors Influencing Drug Metabolism
• Drug interactions

CYP Inhibitors
Strong Increase AUC of sensitive index substrates 5-fold
Moderate Increase AUC of sensitive index substrates ≥ 2 to < 5-fold

CYP Inducers
Strong Decrease AUC of sensitive index substrates by ≥ 80%
Moderate Decrease AUC of sensitive index substrates by ≥ 50% to < 80%

• Other factors
Basics of Drug Transport
• What are membrane transporters?
• Proteins involved with the transport of
their substrates across cell membranes
• Necessary for hydrophilic substances to
cross biomembranes

• Clinical relevance
• Drug-drug interactions
• Drug efficacy
 Solute carrier (SLC)
Transporters in Clinical Pharmacology

ATP-binding cassette (ABC)

Image: Membrane Transporters and Drug Response, Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman &
Gilman's: The Pharmacological Basis of Therapeutics, 13e; 2017. Available at:
https://accessmedicine.mhmedical.com/ViewLarge.aspx?figid=194542521&gbosContainerID=null&gbosid=null&g
roupID=null Accessed: August 12, 2019
P-glycoprotein (P-gp)
• ABC transporter
• Also known as ABCB1
• Encoded by the multidrug resistance gene 1 (MDR1)

P-gp
substrate

Image (adapted from): Roberts AG, Gibbs ME. Mechanisms and the clinical relevance of complex drug-drug
interactions. Clin Pharmacol. 2018 Sep 27; 10: 123-134
P-glycoprotein (P-gp)
• ABC transporter
• Also known as ABCB1
• Encoded by the multidrug resistance gene 1 (MDR1)

P-gp
substrate

Image (adapted from): Roberts AG, Gibbs ME. Mechanisms and the clinical relevance of complex drug-drug
interactions. Clin Pharmacol. 2018 Sep 27; 10: 123-134
Conclusion
• Drug metabolism and transport are complex processes that play a central role in
drug development and clinical care
• More complex and detailed information can be found in the subsequent Module 3
lectures

Topics in Module 3
Pathways of Drug Metabolism
Drug Transport in ADME and Drug Action
P-glycoprotein and Drug Transport
Membrane Transport
Drug Transport Across the Blood Brain Barrier
 Course Directors

Dr. Lisa M. Cordes Dr. William Douglas Figg, Sr

PharmD, BCACP, BCOP PharmD, MBA