Combined effect of rifampicin-induced P-glycoprotein expression and lipopolysaccharide-induced intestinal sepsis on the effective permeability and pharmacokinetics of an anti-malarial candidate CDRI 97/78 in rats

Abstract

1. The study aimed to investigate the influences on the pharmacokinetics (PK) of an anti-malarial drug 97/78 in rats pretreated with orally administered rifampicin and bacterial endotoxin lipopolysaccharide (LPS).

2. In-situ intestinal absorption studies were conducted on rats pretreated with rifampicin and LPS or both to estimate effective permeability (P_eff) of 97/78. In-vivo studies were then conducted to explore 97/78 PK profile under these conditions. In-situ studies revealed that P_eff value decreased to 64% (2.7 ± 0.6) × 10⁻⁴cm/s in rats pretreated with rifampicin. This decrease was further enhanced very significantly to 4.5% (0.19 ± 0.03) × 10⁻⁴cm/s in rats pretreated both with rifampicin and LPS (p<0.05). For PK studies, it was found that relative bioavailability (RB) was decreased to 22.56% in rifampicin-pretreated rats and to 8.02% in rats pretreated both with rifampicin and LPS. About five-fold decrease was observed in systemic exposure (AUC) of 97/78 in rifampicin-pretreated rats. This decrease was further augmented to 12-fold upon rifampicin and LPS pretreatment.

3. Orally administered rifampicin decreased the concentration of 97/78 in circulation. This decrease was further enhanced significantly to a very low level by LPS-induced intestinal sepsis.

• Endotoxin
• in-situ intestinal perfusion
• intestinal absorption
• relative bioavailability
• systemic exposure

Acknowledgements

The authors acknowledge the Director, CSIR–CDRI, for providing facilities and infrastructure for the study. CDRI communication no. is 8922.

Declaration of interest

All authors declare that there are no conflicts of interest to disclose.

The authors are sincerely thankful to the Council of Scientific and Industrial Research (CSIR), New Delhi, India, for providing research fellowships.