Effect of carbamazepine on the pharmacokinetic parameters of CDRI-97/78 following coadministration to rats

Coadministration of 2 or more drugs may result in unexpected toxicity. This study aimed to evaluate the effect of carbamazepine coadministration on the pharmacokinetics of CDRI-97/78, an 1,2,4-trioxane antimalarial agent. Firstly, 97/78 was administered alone and then 97/78 and carbamazepine were coadministered to male and female rats. An revalidated LC-MS/MS method was used for quantitation of 97/63 since 97/78 is instantly and completely converted to 97/63 (an in-vivo active metabolite). The Tmax and Cmax values of 97/63 were 1.75±0.77 h and 862±306 ng/mL in male rats whereas in female rats they were 5.45±0.76 h and 662.75±95.09 ng/mL after a single dose of 97/78 alone. However, following coadministration of 97/78 and carbamazepine, the values for Tmax and Cmax were 1.06±0.16 h and 533±153 ng/mL in male rats and 2.23±1.93 h and 636.5±112.4 ng/mL in female rats. The half life of 97/63 following a single oral dose of 97/78 or coadministration with carbamazepine to male rats was 6.98±0.63 h and 6.64±0.54 h, respectively; the values in female rats were 7.5±0.5 h and 5.48±0.37 h. A statistically insignificant difference (P>0.05) was observed with the student t-test for the pharmacokinetic parameters of 97/63 following oral administration of 97/78 alone or coadministration of 97/78 and carbamazepine except for MRT in female rats. Intersex statistical comparison also showed an insignificant difference for 97/63 following oral administration of 97/78 alone or in combination with carbamazepine except for MRT, which supports coadministration of 97/78 and carbamazepine.