Evaluation of pharmacokinetic differences of acetaminophen in pseudo germ-free rats
- Evaluation of pharmacokinetic differences of acetaminophen in pseudo germ-free rats
- 이수현; 안지혜; 이화정; 정병화
- Gut microflora; Pseudo germ-free rats; Acetaminophen; LC-MS/MS; metabolism; pharmacokinetics
- Issue Date
- Biopharmaceutics & drug disposition
- VOL 33, NO 6, 292-303
- To evaluate the metabolic interaction between host and gut microflora on drug
metabolism, pseudo germ-free rats were prepared with an antibiotics cocktail to change their gut
conditions. The usefulness of the pseudo germ-free model was evaluated for observing the DMPK
of acetaminophen (APAP). Pseudo germ-free rats were prepared by orally administering antibiotic
cocktails consisting of bacitracin, streptomycin and neomycin, and then APAP was orally administered
to control and pseudo germ-free rats. The plasma concentration of APAP and its six metabolites
were quantified using a validated LC-MS/MS method. A non-compartment model estimated the
pharmacokinetic parameters of APAP and its metabolites, and the ratios of the area under curve
(AUC; AUCmetabolite/AUCAPAP) were also observed to evaluate the change of APAP metabolism.
The AUCs of APAP and APAP-Glth (glutathione) were higher and the AUCAPAP-Sul/AUCAPAP
(metabolic efficiency of sulfate conjugation) was lower in pseudo germ-free rats than those in the control
rats. The decrease in metabolic efficiency of sulphate conjugation could result from the reduction
of the sulphate supply, causing an increase of the AUC of APAP and APAP-Glth. The activities of gut
microflora can affect the state of hepatic sulphate for drug conjugation, indirectly leading to characteristic
APAP metabolism. These results indicate that gut microflora may play an important role in
the pharmacokinetics and metabolism of APAP. Thus, the metabolic interaction between host and
gut microflora should be considered upon drug administration and pseudo germ-free rats prepared
in the present study can be competent for investigating the metabolic interaction between host and
gut microflora on drug metabolism.
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