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Study of fabomotizole belonging to p-glycoprotein substrates

Journal: I.P. Pavlov Russian Medical Biological Herald (Vol.25, No. 4)

Publication Date:

Authors : ;

Page : 538-550

Keywords : P-glycoprotein; fabomotizole; pharmacokinetics; rifampicin; verapamil; substrate.;

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P-glycoprotein (Pgp) is a membrane efflux protein transporter with numerous drug-substrates. In addition, a lot of drugs alter the activity of the transporter. It can lead to drug-drug interactions during polypharmacy. Fabomotizole (afobazol) is a Russian anxiolytic drug with neuroprotective activity, applied over a wide range of indications. The drug belongs to a potential substrate of Pgp according to its chemical structure. Aim. The aim of the study was to assess belonging of fabomotizole to Pgp substrates. Materials and Methods. The work was performed on 12 male Chinchilla rabbits. The belonging of fabomotizole to Pgp substrates was evaluated by comparing pharmacokinetic parameters of the test-substance after course administration of known transporter inducers and inhibitors – rifampicin and verapamil respectively. Fabomotizole was administered orally as a single dose of 3.8 mg/kg b.w. and blood was taken from the ear vein after 5, 10, 15, 20, 30, 60, 90, 120 and 240 min followed by it's pharmacokinetic analysis by HPLC. Pharmacokinetic parameters of fabomotizole were manually calculated by a model-independent method. The animals were then divided into 2 groups of 6 rabbits each: the 1st group received verapamil at a dose 20 mg/kg b.w. 3 times a day for 14 days, the 2nd – rifampicin in a similar course and dose. After the administration of Pgp modulators the pharmacokinetics of fabomotizole were re-analyzed. Results. It was found that only the absorption coefficient of fabomotizole in the rifampicin series was significantly reduced by 1.27 times as compared to the parameter of intact animals (90% CI 0.66-0.94, p=0.04322). However, this change was not clinically significant, because 90% CI overlapped the range of 0.80-1.25, noted by FDA. The remaining pharmacokinetic parameters of Pgp marker substrate were not significantly changed in any series. This is evidence that fabomotizole is not a Pgp substrate. The insignificant participation of Pgp in fabomotizole pharmacokinetics testifies that the drug can be administered together with drug-modulators of transporter activity without dose correction. Conclusion. In vivo experiment on Chinchilla rabbits showed that fabomotizole is not a substrate of P-glycoprotein.

Last modified: 2018-01-29 23:51:28