Toxicokinetics and Metabolism Flashcards

Which mathematical model best describes the kinetics of ethanol elimination from the blood at typical intoxicating concentrations?

Answer: Zero-order kinetics (Michaelis-Menten saturation)

At intoxicating ethanol concentrations, liver alcohol dehydrogenase (ADH) is saturated, and ethanol is eliminated at a constant rate (~0.015–0.020 g/dL/hr) independent of concentration — zero-order kinetics.

The concept of 'toxicodynamics' in toxicokinetics/toxicodynamics (TK/TD) modeling refers to:

Answer: The relationship between tissue concentration and the magnitude of toxic effect at the target site

Toxicodynamics describes the concentration-effect relationship — how the concentration of a toxicant at its site of action produces a biological response.

Renal clearance of a weak acid is enhanced by urinary alkalinization because:

Answer: Alkaline pH promotes ionization of the acid, trapping it in tubular lumen and reducing reabsorption

Alkalinization of urine shifts weak acid equilibrium toward the ionized form, which cannot diffuse back across tubular membranes (ion trapping), enhancing urinary excretion.

N-acetylation polymorphism (NAT2) is clinically relevant because 'slow acetylators' are at increased risk for:

Answer: Isoniazid peripheral neuropathy and lupus-like syndrome from procainamide

NAT2 slow acetylators accumulate isoniazid (causing peripheral neuropathy from pyridoxine depletion) and hydrazine/aromatic amine metabolites from drugs like procainamide and hydralazine (causing drug-induced lupus).

Species differences in toxicity are often explained by differences in metabolic activation or detoxification. Acetaminophen is more hepatotoxic in cats than humans primarily because cats:

Answer: Lack adequate UGT1A6 glucuronidation capacity for acetaminophen detoxification

Cats have limited UDP-glucuronosyltransferase (UGT1A6) activity for acetaminophen glucuronidation, forcing more metabolism through the CYP2E1 pathway and producing more toxic NAPQI relative to detoxification capacity.

Which concept explains why repeated exposures to a CYP enzyme inducer (e.g., rifampin) decrease the efficacy of co-administered CYP substrates?

Answer: Increased CYP enzyme synthesis increasing metabolic clearance of the substrate

CYP inducers (rifampin, carbamazepine, phenobarbital) increase CYP transcription via nuclear receptors (PXR, CAR), increasing enzyme synthesis and accelerating clearance of co-administered substrates.