Ten healthy volunteers were fed (1) a control diet for 10 days, (2) the same control diet for 3 additional days and a brussels sprouts and cabbage‐containing diet for the next 7 days, and (3) the control diet for the 10 subsequent days. Antipyrine and phenacetin were administered orally before breakfast on days 7 and 10, respectively, of each dietary regimen. During the test diet period the mean plasma half‐life of antipyrine decreased 13% and the mean metabolic clearance rate increased 11%. While small, these changes were statistically significant, indicating a stimulatory effect of cabbage and brussels sprouts on antipyrine metabolism. The values returned to control levels during the second control diet period. During the test diet period the mean plasma concentration of phenacetin was decreased by 34% to 67% at each time interval from 0.5 to 7 hr after phenacetin administration, and the mean plasma concentration of total (conjugated plus unconjugated) N‐acetyl‐p‐aminophenol (APAP), phenacetin's major metabolite, was increased from 0.5 to 3 hr after phenacetin administration. The concentrations of phenacetin and APAP returned toward control values during the second control diet period. The mean plasma half‐life of phenacetin was not influenced by the dietary changes. These results suggest that the test diet enhanced the metabolism of phenacetin in the gastrointestinal tract and/or during its first pass through the liver. Feeding the test diet increased the mean ratio of conjugated APAP to unconjugated APAP observed in plasma at each time interval from 0.5 to 7 hr after phenacetin administration, suggesting that the diet enhanced the conjugation of APAP.
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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