Time effect of rutaecarpine on caffeine pharmacokinetics in rats

Rohit Kumar Estari; Jin Dong; William K Chan; Miki Susanto Park; Zhu Zhou

doi:10.1016/j.bbrep.2021.101121

Time effect of rutaecarpine on caffeine pharmacokinetics in rats

Biochem Biophys Rep. 2021 Sep 6:28:101121. doi: 10.1016/j.bbrep.2021.101121. eCollection 2021 Dec.

Authors

Rohit Kumar Estari¹, Jin Dong¹, William K Chan¹, Miki Susanto Park¹, Zhu Zhou²

Affiliations

¹ Department of Pharmaceutics and Medicinal Chemistry, University of the Pacific, Stockton, USA.
² Department of Chemistry, York College, City University of New York, NY, USA.

Abstract

Rutaecarpine is reported as a potent inducer of CYP1A2 enzyme in rats. There are natural herbal supplements containing rutaecarpine that are designed to enhance the CYP1A2-dependent removal of caffeine from blood so that people can have coffee later in the day without causing sleep interference. This study aimed to determine the minimum amount of time needed from oral rutaecarpine administration until the observed effect of rutaecarpine on caffeine pharmacokinetics (PK) in 15 male Sprague-Dawley rats. PK parameters for caffeine and its metabolites in the control and rutaecarpine groups were calculated using WinNonlin®. Results showed that orally administered rutaecarpine at 100 mg/kg dose as early as 3 h before oral caffeine administration significantly decreased the oral systemic exposure and mean residence time of caffeine and its metabolites due to decreased caffeine bioavailability (by up to 75%) and increased clearance. The systemic exposure of caffeine and its metabolites were also decreased when caffeine was given intravenously, though this effect was less pronounced than when caffeine was given orally. Although plasma level of rutaecarpine was undetectable (less than 10 ng/mL), rutaecarpine still induced hepatic CYP1A2 activity. Results from 7-methoxyresorufin O-demethylation activity, which is specific to CYP1A2, showed that 3 h after one rutaecarpine oral dose, CYP1A2 activity in rat liver tissue was increased by 3- fold. This finding suggested that rutaecarpine effectively induced CYP1A2 activity in the liver.

Keywords: AHR, aryl hydrocarbon receptor; ANOVA, Analysis of variance; BCA, Bicinchoninic acid; CYP, cytochrome P450; CYP1A2; Caffeine; GI, gastrointestinal tract; MROD, 7-methoxyresorufin O-demethylation; Rat; Rutaecarpine; Time-dependent induction; intravenous, IV; pharmacokinetics, PK.