Lecture #110: Pharmacology: Pharmacokinetics Part 2: Principles of Metabolism, Excretion, and Individual Variation in Response

Define Drug metabolism

Enzyme-catalyzed conversion of drugs into more hydrophilic compounds for elimination

What is the Primary organ of drug metabolism?

Liver

What are Other tissues with metabolic activity?

GI tract, lungs, kidneys, skin, brain

Describe Phase 1 reaction

Oxidation, reduction, hydrolysis introducing or exposing a polar group (OH, NH2, SH, COOH)

What is the Purpose of Phase 1 reactions?

Increase polarity or prepare drug for Phase 2; may inactivate, activate, or create toxic metabolite

What are the Major enzymes for Phase 1?

Cytochrome P450 monooxygenases (CYPs)

Describe Phase 2 reaction

Conjugation of drug or Phase 1 metabolite with endogenous molecule

What is the Purpose of Phase 2 reactions?

Increases hydrophilicity; metabolites usually inactive and easily excreted

What is the role of CYP3A4?

Most abundant CYP isoform; metabolizes ~50% of drugs

What are the metabolic requirements of CYP?

Heme, NADPH, oxygen

What are some characteristics of CYPs?

Located in smooth ER; low substrate specificity; subject to induction/inhibition; genetic polymorphisms

What are some Phase 2 enzymes?

Transferases (UGT, SULT, NAT, GST, methyltransferases)

What is the function of UGT?

Transfers glucuronic acid from UDP-glucuronic acid

What is the function of NAT?

Transfers acetyl group from acetyl-CoA

What is the function of SULT?

Transfers sulfate from 3’ - phosphoadenosine- 5’ -phosphosulfate (PAPS)

What is the function of GST?

catalyzes nucleophilic attack by glutathione (GSH) on electrophilic atoms in xenobiotics or toxic metabolites → neutralization of reactive oxygen species

What is the function of Glycine conjugation (or other AA)?

It is a minor pathway. Conjugates are excreted in urine.

Describe Enzyme induction

Increases enzyme synthesis → ↑ metabolism → ↓ drug levels → ↓ therapeutic effect

Describe Enzyme inhibition

↓ enzyme function → ↓ metabolism → ↑ drug levels → ↑ toxicity risk

What is Pharmacogenomic variability?

DNA polymorphisms alter enzyme function → variable drug metabolism rates

What is the First-pass effect?

Drug metabolized by intestine and liver before reaching systemic circulation → ↓ bioavailability

What is the Enterohepatic circulation?

Drug metabolized → conjugated → secreted in bile → intestinal bacteria cleave conjugate → drug reabsorbed → prolongs effect

Describe Excretion

Removal of drug/metabolites from body, mainly via kidneys

What is the Renal elimination processes?

Glomerular filtration, active tubular secretion, passive tubular reabsorption

What is Glomerular filtration?

Free drug (not protein-bound) filtered into renal tubule

What is Active secretion?

Transporter-mediated secretion into proximal tubule

What is Passive reabsorption?

Lipophilic drugs reabsorbed from distal tubule; ionized drugs excreted

Describe Urinary pH & elimination

Ionized drugs trapped in urine → enhanced excretion; acidic urine traps bases; alkaline urine traps acids

What is a Biomarker for kidney function?

Serum creatinine

What does Creatinine clearance measure?

Estimates GFR (Glomerular filtration rate) → how well the kidneys are functioning 

What is a Low GFR effect on drugs?

Drugs eliminated more slowly → accumulation → toxicity → requires renal dose adjustment

Describe Neonate drug Pharmacokinetics

↓ renal function, ↓ metabolism enzymes, ↓ protein binding, ↑ total body water → altered ADME

Describe Elderly drug Pharmacokinetics

↓ renal & liver function, ↓ muscle mass, ↑ total body fat, ↓ GI motility → altered drug clearance and distribution

What are some Factors causing variation in drug response?

Genetic factors, age, liver/kidney disease, nutrition, circadian rhythm, concurrent drugs

What is the Clinical goal of of pharmacokinetics?

Right drug, right dose, right duration for optimal therapy