Ketoconazole is a possible choice as a positive control CYP3A inhibitor. The scientific value of such studies is strengthened by inclusion of a ‘positive control’ arm, intended to depict the ‘worst case scenario’ DDI.
In the course of drug development, new chemical entities suspected of being CYP3A inhibitors may be evaluated in clinical drug–drug interaction (DDI) studies using midazolam as the in vivo CYP3A probe compound. In contrast, an inhibitor such as ketoconazole, acting on both hepatic and enteric CYP3A, increases AUC of both intravenous and oral midazolam, but the effect on oral midazolam AUC is substantially greater. An enteric-specific CYP3A inhibitor, such as grapefruit juice, has no effect on total area under the plasma concentration curve (AUC) of intravenous midazolam, but increases AUC for oral midazolam by a factor of up to twofold. It is established that incomplete oral bioavailability of midazolam results from a combination of hepatic and enteric CYP3A activity. Under baseline conditions, midazolam undergoes extensive presystemic extraction after oral dosage, with net systemic bioavailability in the range of 30%. The benzodiazepine derivative midazolam, a substrate for biotransformation by cytochrome P450 3A (CYP3A) enzymes, is extensively used in drug development and clinical pharmacology as an index compound to profile the activity of hepatic and enteric CYP3A.
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