In Vivo Inhibition of CYP3A-Mediated Midazolam Metabolism by Anchusan in Rats

Abstract

Abstract. Cytochrome P450 (CYP)-mediated drug interactions caused by Kampo medicine have not been investigated sufficiently. The current study was conducted to reveal the effect of anchusan, a commonly used Kampo formula for gastrointestinal disease, on CYP3A-mediated drug metabolism in rats. The pharmacokinetics of midazolam (MDZ) was investigated after the single or one-week administration of anchusan (500 mg/kg) to evaluate its inhibitory and inducible effect on CYP3A, respectively. MDZ was administrated 16 h after the last anchsan treatment in the multiple dose study, while their intervals were 2 or 16 h in the single dose study. Unexpectedly, the multiple-pretreatment of anchusan increased the AUC of MDZ by 2.4-fold rather than decreasing it, and the CYP3A contents and activities were unchanged in hepatic and intestinal microsomes of these rats. In contrast, no significant inhibitory effects on MDZ metabolism were observed by the single anchusan pretreatment. In vitro study showed that the preincubation of anchusan and some of its component extracts with rat liver microsomes reduced CYP3A activity in a time-and NADPH-dependent manner. These results suggested that anchusan increased the serum MDZ concentration in rats, at least in part, by the time-dependent inhibition of CYP3A.

Emamectin benzoate (Proclaim®) mediates biochemical changes and histopathological damage in the kidney of male Wistar rats (Rattus norvegicus)

“…Cárcamo et al [36] showed that exposure of rainbow trouts to pharmacological EMB concentrations altered the transcriptional responses of xenobiotic biotransformation proteins and extrusion transporters. EMB increases CYP3A expression in kidney and intestine samples and it is wellknown that CYP3A enzymes participate strongly in drug interactions [37,38]. Probably, the lipophilic nature of EMB and its non-biotransformation may lead to its accumulation in the plasma and produce changes in many functions including renal, nerve and hepatic functions.…”

Inhibition of CYP3A-mediated Midazolam Metabolism by <i>Kaempferia Parviflora</i>

“…The serum concentrations of MDZ were determined using previously described HPLC methods with slight modifications 22 , 23 , 24 ) . Briefly, 100 µL of each serum sample was diluted with 500 µL of 0.1 N NaOH, and 5 ng of diazepam was added as an internal standard.…”

Effect of Benifuuki Tea on Cytochrome P450-mediated Metabolic Activity in Rats

“…After the two treatments with Benifuuki tea, MDZ serum concentrations were measured by an HPLC method previously reported by our laboratory (18,19). Briefly, 100 μl of each serum sample was alkalized and extracted with dichloromethane: pentane (1:1) for 1 min in the presence of diazepam as an internal standard.…”