title: 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 (Peff) of 97/78. In-vivo studies were then conducted to explore 97/78 PK profile under these conditions. In-situ studies revealed that Peff value decreased to 64% (2.7 ± 0.6) × 10(-4 )cm/s in rats pretreated with rifampicin. This decrease was further enhanced very significantly to 4.5% (0.19 ± 0.03) × 10(-4 )cm/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.
authors: Pharmacokinetics & Metabolism Division, CSIR - Central Drug Research Institute , Lucknow, Uttar Pradesh , India .
authors: Yeshwant
authors: Y
authors: Singh
authors: Mahendra Kumar
authors: MK
authors: Hidau
authors: Jampala
authors: J
authors: Krishna
authors: Shio Kumar
authors: SK
authors: Singh
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000818:Animals; D000962:Antimalarials / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001682:Biological Availability; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics*; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism; D008070:Lipopolysaccharides / Q000493:pharmacokinetics*; D008297:Male; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012293:Rifampin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018805:Sepsis / Q000139:chemically induced* / Q000188:drug therapy*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000962:Antimalarials; D019086:Bridged Bicyclo Compounds, Heterocyclic; C574493:CDRI-97-78; D008070:Lipopolysaccharides; D012293:Rifampin
keywords: Endotoxin; in-situ intestinal perfusion; intestinal absorption; relative bioavailability; systemic exposure