The pharmacokinetics of midazolam and 1-hydroxymethylmidazolam were investigated following oral administration of 7.5, 15 and 30 mg doses of midazolam in solution to 12 healthy subjects. Compared to the 7.5 mg dose, the Cmax and AUC parameters of both midazolam and 1-hydroxymethylmidazolam increased proportionally after the 15 mg dose and more than proportionally after the 30 mg dose. The t1/2 for midazolam remained relatively constant between the 7.5 and 15 mg doses whereas it increased slightly but significantly after the 30 mg dose. These data indicated that the pharmacokinetics of midazolam and 1-hydroxymethylmidazolam were linear between the 7.5 and 15 mg oral dose range. However, after the 30 mg dose, the systemic availability of midazolam and the AUC for 1-hydroxymethylmidazolam appeared to be greater than that anticipated from the lower doses, possibly due to saturation of midazolam first-pass metabolism. This is not expected to have any clinical significance under the conditions of therapeutic use.

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Eight healthy men received 100 mg oral doses of etretinate separated by two-week washout periods in an open, randomized, crossover study. Etretinate was administered during a complete fast, with a standard high fat breakfast, a standard high carbohydrate breakfast, and 16 ounces of whole milk. Plasma samples were obtained at specific times over a 48-hour period. Plasma concentrations of etretinate as well as two of its major metabolites were determined by a specific, reverse-phase, high-performance liquid chromatography method. Plasma concentrations of etretinate were greater when administered with a high fat meal and whole milk compared to ingestion with a high carbohydrate meal or during a complete fast. In contrast, there was no increase in the plasma concentrations of the active metabolites following any of the meals. These data indicate that chronic dosing of etretinate with milk or a high fat meal compared with fasting conditions will result in higher concentrations of etretinate, which may ultimately lead to higher metabolite concentrations.

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