ABSTRACT
A bioequivalence study of two verapamil formulations [generic verapamil tablets and Isoptin tablets] was performed by comparing pharmacokinetic parameters of the parent drug and its major metabolite, norverapamil following a single dose administration of 80 mg verapamil hydrochloride in 22 healthy volunteers according to a randomized, two-period, crossover-design study. Moreover, the feasibility of proving bioequivalence of verapamil oral dosing form by means of norverapamil pharmacokinetic parameters was evaluated. Concentrations of verapamil and norverapamil were quantified in plasma using a validated high-performance liquid chromatography [HPLC] with fluorescence detection. The 90% CIs for the log-transformed ratios of verapamil C[max] [maximum plasma concentration] and AUC [area under the plasma concentration-versus-time curve from time zero to the infinity] were 73 to 101 and 80 to 103. respectively. Similarly, the corresponding ranges for norverapamil were 80-100 and 84-103, respectively. According to the parent drug data, the 90% confidence intervals around the geometric mean ratio of AUC happened to fit within preset bioequivalence limits of 80-125%, whereas those for C did not. The 90% confidence intervals for both C[max] and AUC of norverapamil met preset bioequivalence limits. The AUC and C[max] of metabolite, when compared to parent drug, showed a much lower degree of variability and the 90% confidence intervals of the metabolite were therefore narrower than those of the parent drug. These observations indicate that bioequivalence studies using metabolite, norverapamil. could be a more suitable and preferable approach to assess bioequivalence of verapamil formulations due to its much lower variability and therefore lower number of volunteers that are required to conduct the study
ABSTRACT
Etoposide, a widely used anticancer drug, exhibits low and variable oral bioavailability mainly because of being substrate for the efflux transporter, P-glycoprotein [P-gp]. Therefore, the present study was aimed to investigate the effect of D-alpha-tocopherol polyethylene glycol 1000 succinate [TPGS] and PEG 400 as P-gp inhibitors on the intestinal absorption of etoposide. Everted sacs of rat small intestine were incubated in Krebs buffer solution which contained etoposide in the absence or presence of various concentrations of TPGS or PEG 400. The effect of verapamil as a known P-gp inhibitor on the absorption of drug was also studied
The absorptive transport of etoposide was significantly enhanced [p < 0.001] in the presence of verapamil [100 [micro]g/mL] and TPGS [over the concentration range of 0.002-0.1 mg/mL], suggesting that the inhibition of P-gp located in the intestine may be involved in the enhancement of etoposide absorption. However, the addition of PEG 400 at various concentrations [0.05, 0.1 and 0.5% w/v] had no effect on the etoposide transport. No significant difference was found between the permeability values in the absence and presence of the maximum concentration of TPGS for two transport markers, lucifer yellow and imipramine, indicating that the enhancement in etoposide permeability in the presence of TPGS was not due to the compromise in tight junctions or membrane integrity of epithelial cells
The results of the study suggest that the use of TPGS as a safe excipient in etoposide formulations may enhance the oral bioavailability of etoposide and result in a predictable oral absorption