Mechanisms of Drug Translocation and Metabolism

Passive diffusion through lipid bilayer

A mechanism of drug translocation across membranes.

Diffusion through aqueous pores

A mechanism of drug translocation across membranes.

Carrier-mediated transport (active/facilitated)

A mechanism of drug translocation across membranes.

Endocytosis

A mechanism of drug translocation across membranes.

Passive diffusion

The most common drug translocation mechanism for small, lipid-soluble, non-polar drugs.

Fick's Law

dQ/dt = (P·K·A·(C1-C2))/w, governing passive diffusion.

L-Dopa

An example of a drug using facilitated carrier-mediated transport.

Penicillin

An example of a drug using active carrier-mediated transport.

P-glycoprotein

Expels drugs from cells, reducing absorption and causing multidrug resistance.

Particle size

Smaller particles result in increased surface area, leading to faster dissolution and absorption.

Partition coefficient

Measures lipid solubility, the ratio of drug concentration in lipid vs. aqueous phases.

Weak acid (pKa=4) in duodenum (pH=6)

99% ionized (using Henderson-Hasselbalch: pH-pKa=2 → [A⁻]/[HA]=100).

Lipinski's Rule of 5

Criteria: MW <500Da, logP ≤5, ≤5 H-bond donors, ≤10 H-bond acceptors.

Food high in fat

Delays gastric emptying, slowing absorption of intestinal-absorbed drugs.

Grapefruit juice

Inhibits intestinal CYP3A4 and P-glycoprotein, increasing drug bioavailability.

Aging

Results in slower gastric emptying, achlorhydria, bacterial overgrowth, leading to decreased absorption.

Eggerthella lenta

A gut bacterium that reduces digoxin absorption.

High Vd (>100L)

Indicates extensive tissue binding (e.g., digoxin Vd=350L).

Vd calculation

Vd = Dose/C = 500/10 = 50L.

Heparin

Vd compartment: Plasma (3.5L).

Gentamicin

Vd compartment: Extracellular fluid (13.5L).

Diazepam

Vd compartment: Total body water (41.5L).

Thiopental

Has a short duration despite high lipid solubility due to redistribution from brain to muscle/fat.

Plasma protein binding

Only free (unbound) drug is pharmacologically active.

Albumin

Binds acidic drugs.

α1-acid glycoprotein

Binds basic drugs.

Polar drugs

Have difficulty crossing the BBB due to tight junctions limiting paracellular transport.

Phase I metabolism

Introduces polar groups.

Phase II metabolism

Conjugates drugs for excretion.

Cytochrome P450 (CYP)

Dominates Phase I metabolism.

Paracetamol toxicity in overdose

Occurs due to saturation of conjugation pathways leading to more NAPQI and glutathione depletion.

Prodrug

Inactive until metabolized (e.g., tamoxifen → endoxifen).

CYP2D6 metabolizer phenotypes

PM, IM, EM, UM (poor to ultrarapid).

CYP2D6 poor metabolizers and tamoxifen

Respond poorly as they can't activate tamoxifen to endoxifen effectively.

Grapefruit juice and felodipine

Inhibits CYP3A4, increasing bioavailability (5x higher levels).

CYP2C92/3 and VKORC1 variants

Genetic variants that affect warfarin dosing.

Renal processes determining drug excretion

Filtration, secretion, reabsorption.

Renal clearance calculation

CL = (Urine concentration × Flow rate) / Plasma concentration.

Alkalinize urine in aspirin overdose

Traps ionized aspirin in urine, increasing excretion.

Enterohepatic recycling

Drug excreted in bile, reabsorbed in gut, prolonging effect.

Warfarin and St. John's Wort

CYP induction leads to faster warfarin metabolism and decreased anticoagulation.

Metoclopramide with migraine drugs

Counteracts gastroparesis, increasing drug absorption.

CYP2D6 poor metabolizer and codeine

Results in reduced morphine production and poor analgesia.