Mephenytoin stereoselective elimination in the rat: II. Comparison of mephenytoin stereoselective clearance during chronic intravenous and hepatic portal vein administration

Abstract

The stereoselective clearances of R- and S-mephenytoin were determined in rats receiving either an intravenous or hepatic portal vein infusion of racemic mephenytoin. The mean +/- SD intravenous clearances of R- and S-mephenytoin were 1630 +/- 250 ml/hr and 630 +/- 250 ml/hr, respectively. The corresponding portal vein clearances for these enantiomers were 2560 +/- 1230 ml/hr (R-mephenytoin) and 540 +/- 230 ml/hr (S-mephenytoin). In spite of the slightly higher clearance for R-mephenytoin following portal vein administration, the difference between the intravenous and portal vein clearances for R- or S-mephenytoin were not found to be significant. Subsequent computer simulations of the data indicated there was less than a 5% probability that this result could be attributed solely to interanimal variability in drug clearance. The estimated extraction ratio of R-mephenytoin by the liver was modest and suggested mephenytoin may undergo a substantial degree of extrahepatic elimination in the rat.

Mephenytoin stereoselective elimination in the rat: III. Stereoselective time course of induction during chronic hepatic portal vein administration

“…The post-induction estimates for the clearance of R-mephenytoin (2400 ± 1600 ml/h) and for S-mephenytoin (440 ± 160 ml/h) were also comparable to the 2500 ± 1200 ml/h (R-isomer) and 530 ± 230 ml/h (S-isomer) reported in a prior study during days 4 and 5 of a portal vein infusion with racemic mephenytoin (17). The marked increase in mephenytoin clearance observed in this investigation reflects a pronounced ability of this drug to increase its own elimination during chronic administration.…”

“…While R-and S-mephenytoin did appear to attain initial steady-state levels quickly, it is unlikely the active metabolite (phenyl ethylhydantoin, PEH) reached steady state concentrations for several days. The PEH metabolite is known to increase oxidative drug metabolism in rats (30), and its levels have been found to exceed those of mephenytoin by 50-150 fold (17). A continued increase in PEH concentrations during these infusions may account for the prolonged time course of induction observed in three of the rats in this study.…”

“…Recent evidence suggests chronic administration of mephenytoin may induce several cytochrome P-450 enzymes in the liver in addition to extrahepatic drug metabolism (15,17). This clearly violates a fundamental assumption necessary for the derivation of the pbannacokinetic model relating cellular changes in enzyme activity to drug clearance (23,26,32).…”

“…One possible explanation for this relationship is that both these parameters may be dependent upon the concentration of PEH. PEH concentrations have been found to vary over a 10 fold range between rats receiving nearly identical infusions of mepbenytoin for 5 days (17). In view of the contribution of PEH to induction of drug metabolism, varying rates and extent of PEH accumulation in blood may influence the time course of induction and the expression pattern of the induced enzymes.…”

“…In rats it is known that chronic mephenytoin administration increases hepatic cytochromes P-450pcn-e, P-450pb-b and P-450pb-c (15).-Furthermore, previous research had also suggested that mephenytoin stereoselective clearance may be altered by its continuous administration to this species (16,17). However, there have been no reports on the time course of change in stereoselective drug elimination due to this process.…”