Depression of phenytoin metabolic capacity by 5-fluorouracil and doxifluridine in rats

Abstract

It has been found in clinical practice that the serum level of phenytoin, of which metabolism is mediated by hepatic CYP2C enzymes, was markedly elevated by co-administration of 5-fluorouracil (5-FU) and doxifluridine (5'-deoxy-5-fluorouridine; 5'-DFUR), a prodrug of 5-FU, but the detailed mechanisms are unclear. A study using rats was undertaken to examine the effects of 5-FU and 5'-DFUR on phenytoin metabolism in hepatic microsomes and phenytoin pharmacokinetics in-vivo. Neither 5-FU nor 5'-DFUR exhibited direct inhibitory effects on hepatic microsomal phenytoin p-hydroxylation, a major metabolic route catalysed by CYP2C in rats, as in humans. 5-FU and 5'-DFUR were injected intraperitoneally into male rats as single doses (1.68 mmol kg(-1)) and repeated doses (0.24 mmol kg(-1) for 7 days). Control rats received vehicle alone. A significant reduction in the activity of phenytoin p-hydroxylation was observed 4 days after the last administration irrespective of the agents and their treatment regimens, although the activity was unchanged on Day 1. Pharmacokinetic analysis of phenytoin revealed that the elimination rate constant and the total clearance was decreased by 70-75% in both the 5'-DFUR-treated and 5-FU-treated rats, indicating that the decrease in the metabolic capacity of phenytoin was responsible for the change in phenytoin disposition in-vivo. On the other hand, 5-FU significantly depressed the total P450 content, NADPH cytochrome c reductase activity and activities of progesterone hydroxylations. However, the depressive effects of 5'-DFUR were not very potent relative to those of 5-FU, which can be explained by the fact that 5-FU is derived from 5'-DFUR to only a small extent. According to a recent report, phenytoin p-hydroxylation and progesterone 2alpha-/21-hydroxylations share common CYP2C enzymes as their catalysts. Because there was a difference in the modulation profiles between phenytoin p-hydroxylation and progesterone 2alpha-/21-hydroxylations after exposure to 5'-DFUR, 5'-DFUR might modulate phenytoin metabolism without loss of catalytic ability for other substrates, unlike 5-FU. The present study suggested that the down-regulation of hepatic CYP2C enzymes occurs by 5-FU exposure even at a low level, and provided a fundamental explanation for the drug interaction encountered in clinical practice.

A dose-escalation study of indisulam in combination with capecitabine (Xeloda) in patients with solid tumours

“…The results suggest that CYP2C9 activity is decreased even after a 7-day dosing interval of capecitabine. This finding is in agreement with the results of Konishi et al (2003), who demonstrated that the decrease in phenytoin p-hydroxylation after single doses of 5-FU or 5 0 -DFUR was not fully resolved after 7 days.…”

PK/PD Model of Indisulam and Capecitabine: Interaction Causes Excessive Myelosuppression

“…Before the first treatment cycle and immediately after the last infusion of 5‐fluorouracil of each cycle, losartan was administered and urine was collected during the following 8 h. In accordance with the results of our study, enzymatic activity was unchanged after cycle 1 but was significantly reduced after cycle 3 26 . In a preclinical study in rats, it was shown that CYP2C9 activity was decreased at day 4 after treatment with capecitabine or its metabolite 5′‐DFUR and was partially recuperated at day 7 27 . The time profile of the enzyme in the pharmacokinetic model was in agreement with this finding, because at the beginning of each cycle and 7 days after interruption of capecitabine treatment, the amount of active enzyme was also partially recovered.…”

“…26 In a preclinical study in rats, it was shown that CYP2C9 activity was decreased at day 4 after treatment with capecitabine or its metabolite 5 0 -DFUR and was partially recuperated at day 7. 27 The time profile of the enzyme in the pharmacokinetic model was in agreement with this finding, because at the beginning of each cycle and 7 days after interruption of capecitabine treatment, the amount of active enzyme was also partially recovered.…”

“…The current study shows that the nonlinear elimination pathway of indisulam was also inhibited by (a metabolite of) capecitabine. As it has often been reported that treatment with capecitabine or 5‐fluorouracil inhibits CYP2C9‐mediated processes, 18 , 19 , 20 , 26 , 27 , 29 , 30 it is quite likely that the Michaelis–Menten elimination rate is proportional to CYP2C9 activity. Both the pharmacogenetic study and this study provide supportive evidence that metabolism of indisulam by CYP2C9 is a saturable process in vivo .…”

Prolonged Pharmacokinetic Interaction Between Capecitabine and a CYP2C9 Substrate, Celecoxib

“…A plausible explanation for this DDI is inhibition of the cytochrome P450 (CYP) 2C9 enzyme, and consequently the metabolism of S ‐warfarin (the main contributor to therapeutic efficacy) to S ‐7‐hydroxywarfarin by 5‐FU. However, 5‐FU does not directly inhibit the hydroxylation of S ‐warfarin or phenytoin, another CYP2C9 substrate. Furthermore, the pharmacodynamic effect experienced by patients is not immediate but takes time to manifest and resolve …”