Pharmacokinetic Interaction between Losartan andRhodiola roseain Rabbits

Abstract

Aim: The study investigates the potential interaction of the herbal medicinal product of Rhodiola rosea on the pharmacokinetics of losartan and its active metabolite EXP3174 after concurrent oral administration to rabbits. Materials and Methods: We conducted a randomized, single-dose, two-treatment, two-period, two-sequence, cross-over pharmacokinetic study on 6 healthy female New Zealand rabbits, after concurrent oral administration of losartan (5 mg/kg) and the herbal medicinal product of R. rosea (50 mg/kg). Quantification of losartan and its main active metabolite EXP3174 was achieved using a validated HPCL/UV method. Pharmacokinetic and statistical analysis was performed using the EquivTest/PK software. Observations: Administration of the herbal medicinal product of R. rosea resulted in a statistically significant increase of the following pharmacokinetic parameters for losartan: the maximum plasma concentration (C_max), the area under the curve (AUC) and the apparent total body clearance (CL/F). An almost 2-fold increase in the AUC of losartan was observed after concurrent administration of the herbal medicinal product of R. rosea. No statistically significant alteration was observed in the pharmacokinetic parameters of the active metabolite of losartan EXP3174. Conclusion: The data of this study suggest that R. rosea significantly alters the pharmacokinetic properties of losartan after concurrent oral administration to rabbits. A study in humans should be conducted to assess the clinical significance of a possible herb-drug interaction between the herbal medicinal products of R. rosea and drugs such as losartan, which are substrates of both CYPs and P-gp.

Rhodiola species: A comprehensive review of traditional use, phytochemistry, pharmacology, toxicity, and clinical study

“…A case report on a 68‐year‐old female patient with recurrent moderate depression developed serotonergic syndrome after taking R. rosea together with paroxetine, indicating a potential pharmacokinetic and dynamic interactions . Concurrent use of R. rosea significantly altered pharmacokinetic properties of losartan in rabbits . It is demonstrated that Rhodiola extracts and some of the constituents such as rhodiosin and rhodionin are potential inhibitors of cytochrome P450 enzymes and P‐gp transporter .…”

In vitro inhibition of cytochrome P-450 activities and quantification of constituents in a selection of commercial Rhodiola rosea products

“…In the study by Panossian et al (2009), no significant inhibition was found in the metabolism of warfarin and theophylline in rats following oral administration of R. rosea. Opposed to this, the study by Spanakis et al (2013), showed a significant inhibition in the metabolism of losartan [CYP3A4, CYP2C9 and CYP2C10 substrate (Sica et al 2005)] in rabbits after oral administration of a R. rosea product. Just recently, we found a 23% reduction in CYP2C9 activity in a cross-over study (including 13 human males) with the commercial R. rosea product Artic Root (Thu et al 2016).…”

“…Five studies have previously been published on CYP inhibition by full extracts of R. rosea (Scott et al 2006;Panossian et al 2009;Hellum et al 2010;Spanakis et al 2013;Thu et al 2016). Hellum et al (2010) showed that ethanol extracts of R. rosea clones (raw plant material) significantly inhibited CYP3A4 in vitro, with IC 50 values ranging from 1.7-3.1 lg/mL.…”

Noncompetitive inhibition of human CYP2C9 in vitro by a commercial Rhodiola rosea product

“…(), who found an almost twofold increase in AUC of the CYP2C9 substrate losartan after a 50 mg/kg concurrent administration of a commercial R. rosea extract to six rabbits in a two‐way crossover study, concluding that R. rosea could be categorized as a moderate in vivo inhibitor and that a study in humans was needed. Recently, our group published a study evaluating CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 interaction in man by a commercially available R. rosea product similar to that used by Spanakis et al (). In this study, using a two‐phase, randomized cross‐over cocktail study in 13 males, we found a 21% reduction in the EXP‐3174/losartan ratio, indicating a significant inhibition of CYP2C9 enzyme activity (Thu et al.…”