The best known effects of barbiturates on the liver are those on the microsomal drug-metabolizing system (see Chapter 3). Acutely, the barbiturates combine with several CYPs and inhibit the biotransformation of a number of other drugs and endogenous substrates, such as steroids; other substrates may reciprocally inhibit barbiturate biotransformations.
Chronic administration of barbiturates markedly induces (approximately doubles) the activities of glucuronyl transferases and CYPs 1A2, 2C9, 2C19, and 3A4, thereby increasing the metabolism of a number of drugs and endogenous substances, including steroid hormones, cholesterol, bile salts, and vitamins K and D, and the barbiturate itself (and thus contributing to tolerance to barbiturates). Many sedative-hypnotics, various anesthetics, and ethanol also are metabolized by and/or induce the microsomal enzymes, and some degree of cross-tolerance therefore can occur. Induction extends to S-aminolevulinic acid synthetase and can cause dangerous disease exacerbations in persons with acute intermittent porphyria.
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