Barbiturates (except for the less-soluble phenobarbital) are mainly metabolized by the liver into inactive, water-soluble compounds by oxidation and then are renally excreted or conjugated to glucuronic acid and excreted in bile. The most significant aspect of the metabolism of barbiturates (e.g., phenobarbital, thiopental, methohexital) is their effect on the hepatic microsomal enzyme system (cytochrome P450 (CYP) enzymes). These effects are dependent on the duration of exposure to the barbiturate. Acutely, barbiturates interact with various CYPs and inhibit the biotransformation of other CYP substrates; likewise, other substrates (e.g., other drugs or endogenous substrates) can inhibit the barbiturate metabolism. Chronic use of barbiturates will cause upregulation, or induction, of the microsomal enzymes (CYPs 1A2, 2C9, 2C19, and 3A4), increasing the metabolism of drugs metabolized by these enzymes. This can lead to patients requiring larger dosages of medication to achieve therapeutic effect and/or increased clearance. This enzyme induction also causes barbiturate tolerance due increased barbiturate metabolism. In addition, barbiturates induce other enzymes, notably δ-aminolevulinic acid (ALA) synthetase. ALA synthetase is involved in the porphyrin production pathway, and therefore barbiturates are contraindicated in patients with acute intermittent porphyria (AIP) or variegate porphyria because they may precipitate an attack, manifested by severe abdominal pain, nausea, vomiting, psychiatric disorders, and neurologic abnormalities.