(8) Drug-drug interactions: Pharmacokinetics (Metabolism & Excretion)

Purpose of Metabolism

Lipophilic drug → metabolism → more hydrophilic metabolite → excretion

• Professor explained that drugs generally need lipophilic properties to enter the body, but urinary excretion favors more hydrophilic/ionized substances.

Phase I vs Phase II

Phase I

• oxidation

• hydroxylation

• reduction

Phase II

• Conjugation

→ another molecule is attached to the drug

What are the main enzymes help metabolize drugs?

• CYP3A4

  • liver → systemic clearance

  • intestinal wall → first-pass metabolism.

Enzyme Inhibition vs Induction

Enzyme Inhibition vs Induction

If it is an ACTIVE DRUG:

Inhibitor → metabolism ↓ → drug ↑

Inducer → metabolism ↑ → drug ↓

Enzyme Inhibition vs Induction

If it is a PRODRUG:

Inhibitor → activation ↓ → active drug ↓

Inducer → activation ↑ → active drug ↑

Why Induction Is Slow?

nuclear receptor activation → gene transcription → RNA → protein synthesis → more CYP enzyme

enzyme induction…

takes days

Professor Drug Examples

overview

• Amiodarone + Warfarin

• Omeprazole + Clopidogrel

• Carbamazepine + Apixaban

• Rifampin + Enalapril

Professor Drug Examples

Amiodarone + Warfarin

Amiodarone = inhibitor

→ warfarin metabolism ↓
→ warfarin level/effect ↑
→ bleeding risk ↑

Professor Drug Examples

Omeprazole + Clopidogrel

Clopidogrel = prodrug

Needs CYP2C19 activation.

Omeprazole inhibits CYP2C19:

clopidogrel activation ↓ → antiplatelet effect ↓ → ischemic event risk ↑

Professor Drug Examples

Carbamazepine + Apixaban

Carbamazepine = inducer

Apixaban = active drug

→ metabolism ↑
→ apixaban level/effect ↓
→ thromboembolic/ischemic risk ↑.

Professor Drug Examples

Rifampin + Enalapril

• Rifampin = inducer.

• Enalapril = prodrug.

• More active drug is initially formed.

• But the active metabolite is also cleared faster.

Net result discussed → antihypertensive effect ↓

Intestinal CYP contributes to…

first-pass metabolism.

CYP inhibition in intestine

metabolism ↓ → AUC ↑ + Cmax ↑

CYP induction in intestine

metabolism ↑ → AUC ↓ + Cmax ↓

Intestinal vs Hepatic CYP

Intestinal CYP
→ mainly affects oral drugs/exposure

Hepatic CYP
→ affects oral AND IV drugs through systemic clearance.

How did professor say to memorize CYP450 and P-gp inhibitors/inducers?

Memorize them together — the listed CYP inhibitors are also P-gp inhibitors, and the listed CYP inducers are also P-gp inducers.

CYP/P-gp inducers (IDK, IF NEED TO MEMORIZE??)

• Rifampin

• Carbamazepine

• Phenytoin

• Phenobarbital/primidone

• St. John's wort

• Dexamethasone.

CYP/P-gp inhibitors (IDK, IF NEED TO MEMORIZE??)

• Amiodarone

• Verapamil

• Diltiazem

• Clarithromycin/erythromycin

• Azole antifungals

• HIV protease inhibitors

• Cyclosporine

• Dronedarone

• Grapefruit juice

Renal Excretion

mechanisms: OVERVIEW

1. Filtration

2. Active secretion

3. Reabsorption

Renal Excretion

Filtration

Depends on:

• free/unbound drug

• GFR

Renal Excretion

Active secretion

transporter-mediated

Renal Excretion

Reabsorption

Affected by:

• urine pH

• flow

• lipophilicity.

Renal Excretion

glomerular function and tubular function - relationship with eac other?

glomerular function and tubular function are independent from each other

Reduced Kidney Function

GFR ↓ → filtration ↓ → renal clearance/ renal drug clearance ↓ → AUC/half-life ↑ → accumulation/toxicity

Reduced Kidney Function

who tend to have this?

older adults because renal function tends to decline with age

Drugs That Reduce Renal Perfusion

• NSAIDs

• ACE inhibitors / ARBs

• Diuretics

Nephrotoxic Drugs (IDK, IF NEED TO MEMORIZE??)

• aminoglycosides

• vancomycin

• cisplatin

• ifosfamide

• iodinated contrast.

Nephrotoxic Drugs

If renal toxicity appears:

• monitor renal function

• reduce dose

• stop/change therapy if needed.

Renal Transporter Interaction

Competition/inhibition of secretion transporter → secretion of another drug ↓ → drug level ↑

Urine pH / Ion Trapping

Professor said excretion works in the…

opposite direction from the absorption concept.

Urine pH / Ion Trapping

Basic drug

acidic urine → drug more ionized → reabsorption ↓ → excretion ↑

Urine pH / Ion Trapping

Acidic drug

alkaline/basic urine → drug more ionized → reabsorption ↓ → excretion ↑

Urine pH / Ion Trapping

example

• Aspirin example

  • Aspirin = acid

  • Sodium bicarbonate → urine becomes alkaline

    • → aspirin ionized ↑
      → reabsorption ↓
      → excretion ↑
      → toxicity ↓.

Enterohepatic Recirculation

think of this as…

“drug recycling.”

Enterohepatic Recirculation

Normally, part of a drug can go through this cycle:

Drug in body → liver/bile → intestine → gut bacteria deconjugate it → drug becomes more lipophilic again → intestine reabsorbs it → drug goes back into the body

same thing:

drug/metabolite → bile → intestine → deconjugation → reabsorption

Enterohepatic Recirculation

If the cycle is disrupted:

reabsorption ↓ → exposure ↓

Resins/charcoal can bind substances in the gut and prevent reabsorption.