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. (August 2015)

• Record Type: Journal Article
• Authors: Singh, Yeshwant; Hidau, Mahendra Kumar; Krishna, Jampala; Singh, Shio Kumar
• Is Part Of: Xenobiotica. Volume 45:Number 8(2015:Aug.)
• Page Start: 731
• Page End: 740
• Publication Date: 2015-08
• Subjects: Metabolism -- Periodicals; Drugs -- Physiological effect -- Periodicals; Food additives -- Periodicals; Chemicals -- Physiological effect -- Periodicals; Biochemistry -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; Metabolism -- Periodicals; 574.133
• DOI: 10.3109/00498254.2015.1017548
• Languages: English
• ISSNs: 0049-8254

Abstract

<abstract> <title>Abstract</title> <p>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).</p> <p>2. <italic>In-situ</italic> intestinal absorption studies were conducted on rats pretreated with rifampicin and LPS or both to estimate effective permeability (<italic>P</italic><sub>eff</sub>) of 97/78. <italic>In-vivo</italic> studies were then conducted to explore 97/78 PK profile under these conditions. <italic>In-situ</italic> studies revealed that <italic>P</italic><sub>eff</sub> value decreased to 64% (2.7 ± 0.6) × 10<sup>−4 </sup>cm/s in rats pretreated with rifampicin. This decrease was further enhanced very significantly to 4.5% (0.19 ± 0.03) × 10<sup>−4 </sup>cm/s in rats pretreated both with rifampicin and LPS (<italic>p</italic><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.</p> <p>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.</p> </abstract>