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Current Molecular Pharmacology

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ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

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Research Article

Evaluation of the Effect of Isobutyl Paraben and 2-ethyl Hexyl Paraben on P-glycoprotein Functional Expression in Rats: A Pharmacokinetic Study

Author(s): Osama Y. Alshogran*, Nour F. Al Ghraiybah and Sayer I. Al-Azzam

Volume 15, Issue 7, 2022

Published on: 30 March, 2022

Article ID: e270122200592 Pages: 9

DOI: 10.2174/1874467215666220127121817

Price: $65

Abstract

Background: Pharmaceutical excipients have been shown to influence drug disposition through modulating transport protein.

Objectives: This study assessed the effect of single dose administration of parabens on the pharmacokinetics (PK) of digoxin, a probe substrate of p-glycoprotein (p-gp), in vivo. Also, the effect of multiple dosing of parabens on p-gp expression was examined.

Methods: Rats were randomized into four groups that received either the vehicle, 25 mg/ kg verapamil, 100 mg/ kg isobutyl paraben, or 100 mg/ kg 2-ethyl hexyl paraben, which was followed by giving 0.2 mg/ kg digoxin via oral gavage. Blood samples were collected at different time points, digoxin concentration was measured using LC/MS-MS, and digoxin PK parameters were estimated. Another set of rats received multiple doses of parabens for 14 days, followed by measuring intestinal and hepatic mRNA expression of p-gp using qRT-PCR.

Results: Single dose administration of verapamil significantly increased Cmax (by 60.4 %) and AUC0-t (by 61.7 %) of digoxin compared to the control group, while the PK parameters of digoxin in rats exposed to parabens were not significantly different from the control. Consistently, the mRNA expression of p-gp in the intestine and liver was not affected by parabens treatment.

Conclusions: The lack of isobutylparaben and 2-ethylhexyl paraben effect on p-gp may suggest the insignificant interaction of parabens with p-gp drug substrates, which could be considered for safety when designing pharmaceutical formulations.

Keywords: Drug-excipient interaction, drug transport, parabens, p-glycoprotein, pharmacokinetics, polymerase chain reaction.

Graphical Abstract

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