Pharmacokinetic Gender-related Difference Of Ofloxacin And The Effect Of Rifampicin On The Pharmacokinetic Of Ofloxacin In Rats

Objective1. To investigate gender-related differences in pharmacokinetics of ofloxacin and its mechanisms;2. To investigate the effect of rifampicin on the pharmacokinetics of ofloxacin.Methods1. The concentrations of ofloxacin in rat plasma and urine were determined after tail vein administration (30mg/kg) by high-performance liquid chromatography (HPLC), and the pharmacokinetic parameters of ofloxacin were calculated with the software of DAS2.0; Mrp2expressed in kidney of male or female rats were was qualitatively and quantitatively detected by immunohistochemistry and flow cytometry, respectively;2. Wistar rats were randomly divided into four groups (n=5). The rats were received ofloxacin alone or in combination with rifampicin by oral or intravenous administration. Blood samples were withdrawn at different time points. The concentrations of ofloxacin in rat plasma was determined by HPLC, and the pharmacokinetic parameters of ofloxacin were calculated with the software of DAS2.0;3. Wistar rats were randomly divided into ofloxacin perfused group and ofloxacin co-administration rifampicin perfused group. The rat single-pass intestinal perfusion technique in situ was applied, and the gravimetry was used to correct the perfusion volume. Ka and Papp were calculated.Results1. The plasma concentrations of ofloxacin at0.5,1,2,4,6and8h after injection in female rats were significantly higher than those in male rate (P<0.05). The total excretion of ofloxacin in males was nearly four times greater than that in females (P<0.05).The half-life of elimination (t1/2β) and the area under the curve values (AUC0-t and AUC0-∞) was greater in females than that in males(P<0.05), total systemic clearance (Cl) was greater in males than that in females (P<0.05). Positive staining for Mrp2was detected in the proximal tubules in male and female rats. The expression of Mrp2in the males was significantly higher than that in female rats (P<0.05).2. The rifampicin could change the pharmacokinetic parameters of ofloxacin significantly after oral administration. The t1/2a of ofloxacin was prolonged by1.52-fold, The Cmax of ofloxacin in the absence rifampicin was13.998mg/L, but was reduced to11.797mg/L in the presence rifampicin. The AUC0-t of ofloxacin was reduced by1.29-fold. But the pharmacokinetic parameters of ofloxacin with or without rifampicin were not found significant difference by intravenous administration.3. Rifampicin significantly reduces the intestine absorption of ofloxacin. The Ka and Papp of ofloxacin were reduced.Conclusion1. Gender-related differences in pharmacokinetics of ofloxacin may be attributed to the differences in the expression of Mrp2in kidney of male and female rats.2. Rifampicin may decrease absorption of ofloxacin, it may change pharmacokinetics of ofloxacin.