(7A) Drug-drug interactions: Pharmacokinetics (Absorption & Distribution)

Pharmacokinetics

what the body does to a drug

PK DDI

one drug alters another drug’s concentration-time profile through ADME.

Absorption DDIs

Give me all the Mechanisms

1. Chelation/complexation

2. Adsorption/binding resin

3. Gastric pH change

4. GI motility

5. P-glycoprotein

6. First-pass metabolism

Absorption DDIs

Chelation/complexation

• Polyvalent cation + drug → insoluble complex → ↓ absorption

• Ca²⁺, Mg²⁺, Al³⁺, Fe²⁺/Fe³⁺, Zn²⁺ with some quinolones/tetracyclines or thyroid replacement; Moxifloxacin + cations

• separate doses

Absorption DDIs

Adsorption/binding resin

• Resin/charcoal traps drug in gut → ↓ absorption

  • Can intentionally treat toxicity —an example of a beneficial DDI.

• Bile-acid sequestrants; separate dosing

Absorption DDIs

Gastric pH change

• Changes ionization, permeability, and solubility → altered Tmax/Cmax and sometimes AUC

• PPIs, H₂ blockers, antacids; avoid/use alternatives

• PPI/H₂ blocker + itraconazole

  • Increased gastric pH → ↓ itraconazole absorption

  • Possible treatment failure

Absorption DDIs

GI motility

• Faster transit shortens contact time; slower transit changes/delays absorption

• Prokinetics, anticholinergics, opioids; monitor response

• Metoclopramide + digoxin

  • Increased motility → ↓ digoxin absorption/exposure

Absorption DDIs

P-glycoprotein

• Efflux pump returns drug to gut and

  ↓ absorption/AUC

• Inhibitor → ↑ absorption/AUC → toxicity risk

• inducer → ↓ absorption/AUC treatment-failure risk

Absorption DDIs

First-pass metabolism

• Inhibition/induction changes metabolism before systemic circulation

• effect depends on active drug versus prodrug

  Change	Active drug	Prodrug
  Enzyme inhibition	↑AUC/toxicity	↓activation/treatment failure
  Enzyme induction	↓AUC/treatment failure	↑activation/toxicity

First-pass metabolism

example

• Clopidogrel = prodrug

• Requires CYP2C19 activation

• CYP2C19 inhibitor → ↓ clopidogrel effect → possible MI/stroke

• Enzyme inducer → ↑ clopidogrel effect → bleeding

Distribution DDIs

What we cover in this topic so far?

• Plasma protein binding

  • newborn bilirubin case

  • albumin/AAG

• Tissue distribution

  • Volume of distribution (Vd)

  • Body-composition changes

    • Hydrophilic versus lipophilic drug distribution

Distribution DDIs

Protein binding

• Only free/unbound drug produces an immediate effect.

• Higher-affinity Drug B displaces Drug A.

• Displacement → ↑ free Drug A → ↑ effect/toxicity

• Proteins that bind drugs

  • Albumin

  • α₁-acid glycoprotein (AAG)

Distribution DDIs

Protein binding - EXAMPLE

• Newborn bilirubin displacement

  • protein-binding displacement caused by antibiotic→ ↑ free bilirubin → crosses immature BBB → kernicterus.

• Albumin

  • ↓ albumin → ↑ free drug → potentially ↑ effect

  • Recognize edema and foamy urine as nephrotic-syndrome clues.

Distribution DDIs

How do AAG changes affect free drug?

↑ AAG → ↓ free drug
↓ AAG → ↑ free drug

Distribution DDIs

Tissue Distribution - Volume of distribution (Vd)

• Vd: extent of drug distribution into tissues.

  • Low Vd: drug remains mainly in plasma.

  • High Vd: drug distributes into tissues.

Distribution DDIs

Tissue Distribution -Body-composition changes

• Newborns have more water → higher Vd for hydrophilic drugs.

Older adults/obesity have more fat → higher Vd and prolonged effects, and accumulation of lipophilic drugs