Drug metabolism

Drug Metabolism

Transformation of drug molecules into more polar compounds to facilitate elimination

Active Metabolite

A metabolite that retains pharmacologic activity (e.g., diazepam → oxazepam) following metabolism 

Prodrug

A medication administered in inactive form that is metabolized to an active form (e.g., codeine → morphine)

Bioactivation

Conversion of a drug into a toxic or reactive metabolite (e.g., acetaminophen → NAPQI)

Major Sites of Metabolism

Primarily liver; also lung, kidney, intestine, skin, placenta, testes, adrenals

Phase I Metabolism

Functionalization reactions introducing/unmasking functional groups (oxidation, reduction, hydrolysis, cyclization, decyclization)

Phase II Metabolism

Conjugation reactions adding polar groups to increase solubility for excretion

Cytochrome P450 Enzymes (CYPs)

Major metabolic enzymes responsible for ~60% of drug metabolism (most commonly hydroxylation) 

CYP Nomenclature

System identifying family (number), subfamily (letter), and isoform (number)

CYP3A4

Most abundant hepatic CYP; responsible for metabolism of most drugs

CYP2D6

Key polymorphic enzyme involved in metabolism of opioids like codeine (converts to active form morphine) and tramadol

FMO (Flavin-containing Monooxygenase)

Phase I enzyme metabolizing amines and thiols, phase 1

Alcohol Dehydrogenase

Converts alcohols to aldehydes (cytosolic), type 1 enzyme

Aldehyde Dehydrogenase

Converts aldehydes to carboxylic acids (mitochondrial); inhibited by disulfiram, phase 1 enzyme

Monoamine Oxidase (MAO)

Metabolizes neurotransmitters; located in mitochondrial outer membrane, phase 1 enzyme

Xanthine Oxidase

Purine metabolism enzyme present in liver and intestine, phase 1 enzyme

Esterases

Phase I enzymes catalyzing hydrolysis (e.g., lidocaine, procaine)

Phase II Conjugation Reactions

Conjugation (make hydrophobic by using functional groups, increases polarity for excretion), reactions catalyzed by transferases

P-glycoprotein (P-gp)

Major efflux transporter (ABC/ATP-binding casette family) reducing drug absorption and increasing elimination

ABC Transporters

ATP-dependent efflux proteins that pump drugs out of cells

Influx/uptake proteins

Help drug enter cell, example= OATP (organic anion transport protein 1 and 2, controls cholesterol/statin synthesis)

Polymorphic CYPs

CYP2D6 (Codeine/opioids, overactive= toxic, underactive= won’t activate drug), CYP2C9 (Warfarin, anticoagulant), and CYP2C19 (omeprazole), expression determines effectivity and toxic levels 

CYP2D6 Metabolizer Phenotypes

UM (ultrarapid metabolizers), NM (normal metabolizers), IM (intermediate metabolizers), PM (poor metabolizers)

Factors Affecting Drug Metabolism

Age, sex, nutrition, disease states, PK (dose, frequency, route), exposure to xenobiotics

Drug-Drug Interaction

A measurable modification of one drug’s action by another taken previously or concurrently

Pharmaceutical Interaction

Drug incompatibility outside the body (oxidation, drug mixing, etc)

Pharmacokinetic Interaction

Effects on absorption, protein binding, metabolism, transport, or renal excretion

Pharmacodynamic Interaction

Interactions at receptor sites causing antagonism or potentiation

Enzyme Inhibition

Reduction in metabolic activity → increased drug exposure

Enzyme Induction

Increased metabolic enzyme expression → decreased drug exposure

CYP Inhibitors

Examples: grapefruit juice, ketoconazole, fluconazole, clarithromycin

CYP Inducers

Examples: St. John’s wort, rifampicin, carbamazepine, phenytoin, cigarette smoke