Bioequivalence Of Cefditoren In Human And Its Pharmacokinetics In Rat

We investigated bioequivalence of cefditoren (CDTR) between cefditoren pivoxil (CDTR-PI) tablet (R) and CDTR-PI granule (T) with 24 healthy male volunteers in a randomized cross over design and examined the intestinal absorption of CDTR-PI to CDTR in isolated rat intestine using high performance liquid chromatography (HPLC) and LC-MS methods to determine plasma and other biological samples concentration of CDTR and CDTR-PI. Cmax of T and R were 1.922±0.529μg·ml^-1 and 1. 950±0.582μg·ml^-1 ; AUC0→8h of T and R were 6.337±2.083μg·ml^-1·h-1 and 6.012±1.957μg·ml^-1·h-1 , respectively. The pharmacokinetic parameters showed bioequivalence between T and R in human. The hydrolysis of CDTR-PI into CDTR in rat intestine was inhibited obviously by Orlistat, which is an inhibitor of esterase. It suggested that CDTR-PI was biotransformed to CDTR in rat small intestine by the esterase in intestinal wall.As CDTR was similar to Cephalexin (CEX) in chemical structure, a challenge experiment was also examined to understand whether the absorption of CDTR in rat intestine was mediated by oligopeptide transporter(PepT1). 3 known substrates for PepT1: Cephalexin (CEX), glycylsarcosine (Gly-Sar) and JBP485 (dipeptide) were used as the inhibitors for the absorption of CDTR in the rat small intestine.We also examined the pharmacokinetics of CDTR in liver and kidney of rats with the isolated hepatocytes and kidney slices. We found that CDTR was mainly eliminated by bile. The present study examined the possible role of transporters in the renal uptake process of CDTR. Uptakeof CDTR by kidney slices was shown a saturable process and inhibited potently by PAH, PCG, probenecid and glycylsarcosine (Gly-Sar). These results illustrated that rOat1, rOat3 and Pept1 were involved in the uptake of CDTR by kidney slices.