Pharmacokinetics and food interaction of MK-462 in healthy males.

A study was conducted to assess the safety, tolerability, and pharmacokinetics of single intravenous (IV) doses of 5-90 mu g kg(-1) of MK-462, and the effect of food on the pharmacokinetics of MK-462 administered orally to healthy males. Results of this study indicate that IV doses of MK-462 from 5 to 90 mu g kg(-1) are well tolerated. The disposition kinetics of MK-462 were linear for IV doses up to and including 60 mu g kg(-1). The values of the plasma clearance (CL), steady-state volume of distribution (V-ss), plasma terminal half-life (t(1/2)), and mean residence time in the body (MRT) of MK-462 averaged 1376 mL min(-1), 140 L, 1.8 h, and 1.7 h, respectively, and remained essentially constant over the dosage range of 10-60 mu g kg(-1) of IV MK-462. However, as the dose increased from 60 to 90 mu g kg(-1), the mean value of the apparent CL decreased from 1376 to 807 mt min(-1). Thus, elimination of MK-462 was dose dependent in this dosage range. Based on the disposition decomposition analysis (DDA), it was shown that the V-ss value of MK-462 remained essentially constant over the dosage range of 10-90 90 mu g kg(-1) of IV MK-462. The following values of two dose-independent parameters were also calculated by using DDA: distribution clearance (CL(d)) = 2028 mL min(-1), and mean transit time in the peripheral tissues (MTT(T)) = 0.74 h. The mean values of AUG, C-max, t(max), and apparent t(1/2) of MK-462 in 12 subjects each receiving a 40 mg tablet of MK-462 without breakfast were 330 ng . h mL(-1), 77 ng mL(-1), 1.6 h, and 1.8 h respectively. Although administration of a standard breakfast prior to dosing increased the AUC value (by similar to 20%) of MK-462 and delayed its absorption, there were no significant effects of the meal on the values of C-max and apparent t(1/2) of MK-462.