Solid state NMR and bioequivalence comparison of the pharmacokinetic parameters of two formulations of clindamycin.

OBJECTIVE: The purpose of this study was to compare the pharmacokinetic parameters and determine the bioequivalence of a generic formulation of clindamycin that is sold in the local markets in the Middle East (Clindox® 150 mg capsule; test) with a reference formulation (Dalacin C® 150 mg capsule) in healthy adult male volunteers. METHODS: A single-dose, open-label, 2-period crossover study was conducted. Healthy male volunteers were randomly assigned to oral administration of a single treatment of the reference and test formulations. The same groups were given the alternate formulation. After dosing, serial blood samples were withdrawn for a period of 24 h. Serum harvested from the blood samples was analyzed for clindamycin by high performance liquid chromatography (HPLC) with ultraviolet detection. Pharmacokinetic parameters, including AUC(0-∞), AUC(0-t), C(max), K(e), tmax and t(1/2) were determined from the serum concentrations for both formulations (test and reference). The products were tested for bioequivalence after log-transformation of the data. RESULTS: 24 healthy adult male volunteers from Jordan (mean [SD] age, 28.8 (7.7) years (range 19 - 45 years); height, 175.8 (10.6) cm (range 159.0 - 192.0 cm); weight, 75.6 (11.0) kg (range 58 - 101 kg); and body mass index, 24.4 (1.8) kg/m² (range 21.3 - 28 kg/m²) were enrolled in and completed the study. The 13C NMR spectra for both Dalacin C® and Clindox® showed 18 distinct lines associated with the 18 different carbon atoms. CONCLUSION: The statistical comparison suggested that Clindox® capsules are bioequivalent to Dalacin C® capsules. The 13C CPMAS results confirmed that the two drugs exhibit typical clindamycin spectra.

Mephenytoin stereoselective elimination in the rat: III. Stereoselective time course of induction during chronic hepatic portal vein administration.

The blood concentrations of R- and S-mephenytoin were followed in seven rats over a 5-8 day period during a hepatic portal vein infusion of racemic mephenytoin. In all but two rats, both of the enantiomers achieved an initial steady-state level before a measurable change was observed in their blood concentrations. In each case, the decrease in the initial S-mephenytoin steady state blood level occurred after the change in R-mephenytoin was apparent. During the period of study, the mean +/- SD portal vein clearance of S-mephenytoin increased from 96 +/- 33 ml/h to 450 +/- 160 ml/h. The mean +/- SD portal vein clearance of R-mephenytoin increased from 170 +/- 50 ml/h to 2400 +/- 1600 ml/h. The larger increase in the portal vein clearance for the R-enantiomer resulted in the R/S-mephenytoin clearance ratio over this same time period changing from 1.8 +/- 0.2 to 5.2 +/- 1.8. Attempts to describe the time course of change in the clearance of S- or R-mephenytoin using a previously reported model of induction were unsuccessful. The induction time course did suggest, however, that the rate of induction may be similar for each enantiomer.

Mephenytoin stereoselective elimination in the rat: II. Comparison of mephenytoin stereoselective clearance during chronic intravenous and hepatic portal vein administration.

The stereoselective clearances of R- and S-mephenytoin were determined in rats receiving either an intravenous or hepatic portal vein infusion of racemic mephenytoin. The mean +/- SD intravenous clearances of R- and S-mephenytoin were 1630 +/- 250 ml/hr and 630 +/- 250 ml/hr, respectively. The corresponding portal vein clearances for these enantiomers were 2560 +/- 1230 ml/hr (R-mephenytoin) and 540 +/- 230 ml/hr (S-mephenytoin). In spite of the slightly higher clearance for R-mephenytoin following portal vein administration, the difference between the intravenous and portal vein clearances for R- or S-mephenytoin were not found to be significant. Subsequent computer simulations of the data indicated there was less than a 5% probability that this result could be attributed solely to interanimal variability in drug clearance. The estimated extraction ratio of R-mephenytoin by the liver was modest and suggested mephenytoin may undergo a substantial degree of extrahepatic elimination in the rat.

Mephenytoin stereoselective elimination in the rat: I. Enantiomeric disposition following intravenous administration.

The stereoselective disposition of mephenytoin was characterized after an intravenous bolus dose of racemic mephenytoin to rats being infused with 50% polyethylene glycol 400/50% saline via the jugular and hepatic portal vein. No significant influence on mephenytoin disposition was noted due to the site selected for the administration of the 50% polyethylene glycol 400 solution. The mean (+/- SD) clearance of R- and S-mephenytoin were 171 +/- 58 ml/hr (R) and 110 +/- 37 ml/hr (S), and the mean (+/- SD) volumes of distribution were 325 +/- 75 ml (R) and 359 +/- 72 ml (S). The clearance of R-mephenytoin was significantly larger than the clearance of S-mephenytoin, but this stereoselective difference is of opposite stereochemistry and of much smaller magnitude than the stereoselective difference reported for these enantiomers in man. The difference in the volumes of distribution of R- and S-mephenytoin was not significant.

Method for chronic portal vein infusion in unrestrained rats.

Surgical procedures for the chronic cannulation of the portal and the femoral veins in the rat are described. The surgical procedure for portal vein cannulation is delicate and requires practice, but has proven useful for chronic drug administration. Cannulation of the femoral vein was less involved and cannula patency was extended by proper cannula preparation and placement. This dual cannulation of the rat allowed infusion of racemic mephenytoin into the portal vein and blood collection from the femoral vein for characterizing blood concentrations of the individual isomers. Chronic portal vein drug infusions may provide a useful approach to studies of time-dependent change in hepatic metabolism and stereoselective first-pass drug elimination in unrestrained animals.