EFFECT OF 30-DAY ADMINISTRATION OF CELLGEVITY® ON SELECTED RAT LIVER CYP450 ENZYME ACTIVITY AND POSSIBLE INTERACTION WITH CARBAMAZEPINE

ABSTRACT

Background: There is considerable evidence that many patients concurrently take conventional drugs with dietary supplements or herbal products. One such supplement, with an amalgam of extracts, is Cellgevity®. There is, however, a dearth of information on the effect of this supplement on drug metabolizing enzymes, and on the pharmacokinetics of conventional drugs. Aim: To determine the effect of Cellgevity® on the activity of rat liver CYP1A1/2, CYP3A4, CYP2B1/2, CYP2C9 and CYP2D6 enzymes, and potential effect on the pharmacokinetics of carbamazepine. Methodology: Male and female Sprague-Dawley rats (Hsd:SD strain), weighing 150-200 g and 6-8 weeks old were put into five groups (3 males and 3 females per group). Group 1 was administered with the vehicle (distilled water), that was, solvent used in dissolving Cellgevity® (negative control). Groups 2, 3 and 4 were administered a suspension of Cellgevity® by oral gavage at a low dose (38.63 mg/kg), medium dose (77.25 mg/kg) and high dose (154.50 mg/kg) daily, respectively. Group 5 was administered phenobarbital (15 mg/kg) as positive control. After a 30-day administration period, the animals were sacrificed and livers harvested. Microsomal preparations from rat livers were made by homogenization and differential centrifugation. The substrates of each specific CYP was added to microsomal preparation in phosphate buffer (pH 7.4) and incubated at 37oC and their metabolites measured using fluorometric and chromatographic assays for CYP3A4, CYP2B1/2, CYP1A1/2, CYP2C9 and CYP2D6. Modulation of enzymes by Cellgevity® treatment was determined by comparing enzyme activity of Cellgevity®-treated animals with enzyme activity of negative control animals. The effect of Cellgevity® on the pharmacokinetics of carbamazepine in healthy male SD rats was also investigated. Rats were put into 2 groups consisting of 5 rats in each group. Group 1 was given only Cellgevity® (77.25 mg/kg, po) with normal saline and Group 2 was administered with Cellgevity® (77.25 mg/kg, po) and carbamazepine (80 mg/kg po) concurrently. Treatment was done for 14 days and blood sampled at 0.5, 1, 4, 12 and 24 h from each rat on the 15th day. Blood samples were centrifuged, and serum obtained. Analyses for the levels of carbamazepine in serum (pooled) corresponding to each time point for each group were done by Fluorescence Polarization Immunoassay. Non-compartmental pharmacokinetic analysis was used to estimate pharmacokinetic parameters for the 2 groups. The pharmacokinetic parameters: Cmax, Tmax, AUC, Ke and t1/2 estimation was done by non-compartmental analysis using GraphPad Prism 8.0. Results: Data from the current study showed that on a whole Cellgevity® increased activity of rat liver CYP3A4, CYP2B1/2, CYP1A1/2, CYP2C9 and CYP2D6. However, the increase in enzyme activity of CYP1A1/2, CYP2C9 and CYP2D6 by Cellgevity® was found to be statistically significant. Amongst treatment groups with statistically significant increase in enzyme activity, it was found that, CYP activity modulation by Cellgevity® was dose dependent for female groups of CYP1A1/2, CYP2C9 and CYP2D6, and combined sex group of CYP2C9. The pharmacokinetic parameters for SD rats administered carbamazepine with Cellgevity® vis-a-vis rats administered carbamazepine with normal saline were as follows: Cmax; 20 μmol/L vrs 11 μmol/L, AUC0→24; 347 μmol.h/L vrs 170 μmol.h/L, Ke; 0.3 h-1 vrs 0.4 h-1, and t1/2; 2.3 h vrs 1.7 h, respectively. Conclusion: A 30-day treatment period with Cellgevity® among rats led to a significant increase in the enzyme activity of CYP1A1/2, CYP2C9 and CYP2D6. From the study, it was evident that Cellgevity® altered the pharmacokinetics of carbamazepine in SD rats.