Toxicokinetics and Biotransformation
ADME and the mathematics of exposure
Toxicokinetics describes absorption, distribution, metabolism, and excretion. Master first-order versus zero-order (saturated) kinetics, volume of distribution, clearance, half-life, AUC, bioavailability, two-compartment behavior, and enterohepatic cycling. Biotransformation: Phase I reactions (CYP450 oxidation, reduction, hydrolysis) generally increase polarity and can create reactive intermediates; Phase II conjugation (glucuronidation, sulfation, glutathione, methylation, acetylation) increases water solubility and excretion. Metabolism may detoxify or bioactivate.
Traps: half-life is derived, t1/2 = 0.693 × Vd/CL, so a change in Vd alters half-life without changing clearance. Zero-order kinetics (ethanol, high-dose phenytoin, high-dose aspirin) cause disproportionate concentration rises. Inhibition is immediate and may be competitive or noncompetitive; induction requires transcription and is slow, sometimes autoinducing. Genetic polymorphisms (CYP2D6, NAT2, TPMT) explain idiosyncratic responses. Classic bioactivations: acetaminophen to NAPQI via CYP2E1/3A4, methanol to formic acid, benzo[a]pyrene to a diol epoxide, aflatoxin B1 to the 8,9-epoxide.
Rule of thumb: first-order drugs reach steady state in about 4 to 5 half-lives; loading dose = (Vd × target concentration)/bioavailability. For Vd 50 L, target 2 mg/L, and F 0.5, the loading dose is 200 mg.