Classic histamine H1 receptor antagonists: a critical review of their metabolic and pharmacokinetic fate from a bird's eye view.

摘要: The so-called "classic" histamine H(1) receptor antagonists are highly lipophilic compounds associated with significant biotransformation and tissue distribution. They categorized according to their chemical structure into ethanolamines, alkylamines, ethylenediamines, piperazines, phenothiazines piperidines, all of which have characteristic metabolic fates. former four categories undergo primarily cytochrome P450-mediated oxidative N-desalkylations deamination whereas the aromatic rings latter two hydroxylation and/or epoxide formation. common tertiary amino group is susceptible metabolism by flavin containing monooxygenases forming N-oxides, alicyclic amines produce small amounts (up 7%) N-glucuronides in humans. Species, sex racial differences pharmacokinetics antihistamines known. Specific P450-isozymes implicated were identified a few cases, such as CYP2D6 that contributes promethazine, diphenhydramine chlorpheniramine. Low circulating plasma concentrations part explained first-pass effect Antihistaminic effects last up 6 hours though some exhibit longer duration action due active metabolites. Importantly, inhibited leading clinically drug-drug interaction metoprolol. Other classic shown be potent vitro inhibitors CYP3A4. prescription-free access most can easily lead co-administration other drugs metabolized same enzyme system thereby drug accumulation adverse effects. In depth knowledge pathways enzymes involved crucial prevent high incidence interactions humans, predictable based on pre-clinical data but unexpected when unavailable.