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Xenobiotica ; 45(8): 731-40, 2015.
Article in English | MEDLINE | ID: mdl-25798741

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.


Subject(s)
Antimalarials/pharmacokinetics , Antimalarials/therapeutic use , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Lipopolysaccharides/pharmacokinetics , Rifampin/pharmacokinetics , Sepsis/chemically induced , Sepsis/drug therapy , ATP Binding Cassette Transporter, Subfamily B/metabolism , Animals , Biological Availability , Intestinal Absorption/drug effects , Intestinal Mucosa/metabolism , Male , Permeability/drug effects , Rats , Rats, Sprague-Dawley , Rifampin/therapeutic use
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