ASSESSMENT OF PRESYSTEMIC FACTORS ON THE ORAL BIOAVAILABILITY OF RIFAMPICIN FOLLOWING MULTIPLE DOSING

This study was carried out to elucidate the possible mechanism(s) resp onsible for reduced oral rifampicin bioavailability after multiple dos ing. In addition to autoinduction, the relative contribution of the tw o possible controlling factors, e.g., intestinal metabolism and microb ial degradation, was investigated using a rat model. Pharmacokinetic s tudies were carried out to assess the absolute rifampicin bioavailabil ity by both oral and intravenous drug administration before and after 8 daily doses of 25 mg/kg, To estimate the possible involvement of mic robial degradation, rifampicin kinetics were also assessed in rats on day 8 after receiving multiple oral dosing and concurrent administrati on of nonabsorbable triple antibiotics for gut sterilization 3 days pr ior to the study day. Pharmacokinetic parameters were generated by non compartmental analysis, The results revealed a significant decrease in rifampicin levels for rats after multiple exposure, compared to singl e dosing; the mean clearance determined by intravenous dosing increase d by 43% from 3.7 ml/min/kg and the half-life decreased by 24% from 23 8 min, However, the extent of decrease in rifampicin exposure followin g multiple dosing was substantially greater for rats dosed orally than intravenously; estimated absolute oral bioavailability decreased by 1 5% from 0.89 on day 1 to 0.76 on day 8, No apparent alterations in any of the pharmacokinetic parameters were observed after gut sterilizati on, suggesting minimal contribution of microbial degradation to the re duction in oral rifampicin absorption after multiple dosing. In additi on to hepatic enzyme autoinduction, these results strongly suggest the involvement of enhanced intestinal metabolism as a contributing facto r to the decrease in oral rifampicin bioavailability following prolong ed exposure.