The Effect of Bucolome, a CYP2C9 Inhibitor, on the Pharmacokinetics of Losartan

Abstract

Losartan, a selective angiotensin receptor antagonist, is mainly metabolized by CYP2C9 to an active carboxylic acid, E3174, which is pharmacologically more potent inhibitor than the parent compound. We evaluated the effect of bucolome, a CYP2C9 inhibitor, on the pharmacokinetics of losartan and E3174, which were measured by high performance liquid chromatography in human volunteers and rats. A randomized crossover design study with two phases was done in the volunteer study. In the first phase, the volunteers received losartan 25 mg alone orally (LOS group), and, in the second phase, losartan 25 mg was given after repeated oral administration of 300 mg bucolome for 7 days (LOS+BUC group). In the LOS group, the maximum concentration (C(max)) and area under the concentration curve (AUC) of losartan were significantly higher than in the LOS+BUC group. On the other hand, in the LOS+BUC group, the C(max) and AUC of E3174 were significantly lower than in the LOS group. In the rat study, male Wistar ST rats were used. In the first phase, the rats orally received losartan 10 mg/kg alone or after bucolome was given repeatedly at a dose of 20, 50, or 200 mg/kg for 7 days. In the second phase for steady state, the rats were given losartan 10 mg/kg for 14 days (group A) or losartan 10 mg/kg and bucolome 50 mg/kg for 14 days (Group B). Bucolome at doses 50 and 200 mg/kg significantly increased the AUC losartan and significantly decreased the AUC of 3174. At the steady state, there were no significant differences in AUC of losartan between Group A and B, but the C(max) and AUC of E3174 were significantly lower in Group B than Group A.

Effects of ticlopidine on pharmacokinetics of losartan and its main metabolite EXP-3174 in rats

“…The protein homologies between CYP2C and 3A in rats and humans have been reported to be very similar, 73% and 77%, respectively [28] . For example, the AUC losartan and AUC EXP-3174 were significantly increased and decreased, respectively, by administration of bucolome, a CYP2C9 inhibitor, in both rats and humans [16] . This result supports that rat isoforms with very similar enzymatic properties to CYP2C9 could be involved in the metabolic clearance of losartan in rats, although rats do not have the CYP isoforms orthologous to human CYP2C9.…”

“…In previous pharmacokinetic studies, losartan was administered to rats orally at doses of 3-10 mg/kg [15][16][17] . Thus, a 9 mg/kg dose of losartan was used in the present study.…”

Pre-treatment with Curcumin Enhances Plasma Concentrations of Losartan and Its Metabolite EXP3174 in Rats

“…The dosages of curcumin and losartan used in study were based on similar researches, 22,23) respectively. The pharmacokinetic behaviors of losartan and EXP3174 were described using non-compartment model.…”

Characterization of Bucolome N-Glucuronide Formation: Tissue Specificity and Identification of Rat UDP-Glucuronosyltransferase Isoform (s)

“…This drug is used to treat rheumatoid arthritis because it exhibits analgesic and anti-inflammatory effects without a sedative or hypnotic effect, unlike many other barbiturates [1]. The drug has recently been clarified to inhibit CYP2C9, and potentiation and prolongation of the duration of actions of concomitant drugs and inhibition of metabolite production by combination with BCP have been investigated [2][3][4]. However, BCP-metabolizing enzymes have not been investigated in detail.…”