ABSTRACT
The study aims to evaluate the effect of long-term pretreatment of the rat with Wuzhi tabletï¼WZï¼ on hepatic and intestinal CYP3A mRNA and protein expression and activity. Male Sprague-Dawley rats were orally administered of midazolam (2 mg·kg-1) with or without 14 days of pretreatment of WZ (0.25 g·kg-1) to determine CYP3A activity. Meanwhile, RNA and protein of rats liver and intestine samples were prepared 24 h after the last dose of 14 days of WZ treatment to determine CYP3A mRNA and protein expression. Long-term treatment of WZ increased the mRNA expression of hepatic Cyp3a1, Cyp3a9 and intestinal Cyp3a9 by 54.6%, 188.3%ï¼P < 0.05ï¼ and 48.2%ï¼P < 0.05ï¼, respectively; and increased the protein expression of hepatic CYP3A by 43.2%. However, after long-term treatment of WZ, the AUC of orally administered of midazolam in the WZ group was increased 29.9%ï¼WZ pretreatment groupï¼ and 154.2%ï¼WZ coadministered groupï¼ compared to that of control group. In conclusion, long-term treatment of WZ increased the m RNA and protein expression of CYP3A, while could inhibit the activity of CYP3A.
Subject(s)
Cytochrome P-450 CYP3A/metabolism , Drugs, Chinese Herbal/pharmacology , Midazolam/pharmacology , Animals , Intestines/enzymology , Liver/enzymology , Male , Rats , Rats, Sprague-Dawley , TabletsABSTRACT
Tacrolimus (TAC) is an immunosuppressant that has been widely used alone or in combination with prednisone (PRED) to prevent acute rejection after organ transplantation. Wuzhi tablet (WZ, Schisandra sphenanthera extract) is often prescribed with TAC to prevent drug-induced hepatitis. We recently reported that WZ could significantly increase TAC blood exposure by inhibiting P-gp-mediated efflux and CYP3A-mediated metabolism of TAC. PRED is also a substrate of P-gp and is a weak inducer of CYP3A, and drug-drug interactions within this combination therapy might occur. Therefore, the purpose of this study was to investigate the effect of long-term treatment of WZ and PRED on the pharmacokinetics of TAC in rats. After 14 days of co-administration of WZ and PRED, the AUC(0-24h) of oral TAC was increased (from 59.6±37.3 to 95.3±39.4 ng h/ml, p=0.18) and the clearance was decreased (from 38.4±28.4 to 17.7±6.4 l/h/kg, p=0.15). When only co-administered with WZ, AUC(0-24h) of TAC was demonstrated a significantly increase (from 59.6±37.3 to 135.9±34.8 ng h/ml, p<0.05). The concomitant administration of PRED resulted in a reduction in the systemic exposure of TAC and an increase in its clearance, though neither was statistically significant. Thus, our study suggested that the presence of WZ and PRED still could increase the systemic exposure of TAC in rats. The drug-drug interactions among this combination therapy should still be taken into consideration in clinical practice.