Effect of diphenylhydantoin on hepatic drug hydroxylation

1 Antipyrine total clearance and the formation clearance of its major metabolites were studied in normal, healthy male volunteers before and after multiple dosing for approximately three weeks with phenytoin (six subjects) and carbamazepine (six subjects). 2 Total antipyrine clearance increased on average by 91% after phenytoin dosing and by 61% after carbamazepine and individual increases correlated well with mean plasma concentrations of the anti-epileptic drug. 3 The increase in total clearance resulted largely from increased formation clearances of the 4-hydroxy and 3-hydroxymethylantipyrine metabolites with minimal effect on the norantipyrine pathway, following treatment with both enzyme-inducing drugs. 4 It is concluded that both phenytoin and carbamazepine have similar effects on antipyrine metabolism and that these effects are mediated by induction of specific forms of cytochrome P450.

Section: Discussionsupporting

confidence: 89%

Section: Discussioncontrasting

confidence: 67%

Antipyrine metabolite kinetics in healthy human volunteers during multiple dosing of phenytoin and carbamazepine.

Shaw¹,

Houston²,

Rowland³

et al. 1985

“…Reduction in steady-state CBZ concentrations have previously been reported and theoretically may result in loss of therapeutic effect (Eichelbaum et al, 1975). The phenomenon of autoinduction is not unique to CBZ and has been reported also for glutethimide (Schmid et al, 1964), phenytoin (Petruch et al, 1974) and rifampicin (Acocella et al, 1978). CBZ autoinduction may be described by a pharmacokinetic model which is governed by an induction rate constant (Pitlick et al, 1976).…”

Section: Discussionmentioning

confidence: 92%

Hepatic enzyme induction and leucocyte delta‐aminolaevulinic acid synthase activity: studies with carbamazepine.

Rapeport¹,

McInnes²,

Thompson³

et al. 1983

1 Antipyrine metabolism, daily urinary 6-,3-hydroxycortisol excretion, carbamazepine (CBZ) halflives and leucocyte delta-aminolaevulinic acid synthase (ALA.S) activities were measured following 2 weeks' treatment with CBZ 400 mg and 600 mg once daily in eight healthy male volunteers. 2 Dose-dependent induction of antipyrine metabolism was demonstrated but cortisol hydroxylation appeared maximally induced by the 400 mg dose. 3 CBZ half-lives fell significantly in both studies (P < 0.01 in each case) but a greater fall was seen with the higher dose (P < 0.01). Plasma CBZ concentrations were higher following the eighth doses (P < 0.01) in both studies. 4 Leucocyte ALA.S activity increased by a mean of 657% following 1 week's treatment with 400mg CBZ and 1145% on the 600 mg dose. In both studies ALA.S activities fell towards baseline during the second week of treatment. 5 CBZ possesses potent dose-dependent hetero-and auto-inducing properties. 6 Leucocyte ALA.S activity may represent a novel in vivo index of extrahepatic enzyme induction in man.

“…Increased rate of drug clearance in patients on antiepileptic drugs have been reported (Petruch, Schuppel & Steinhilber, 1974;Welch, DeAngelis, Wingfield & Farmer, 1975;Neuvonen, Penttila, Lehtovaara & Aho, 1975;Stevenson, O'Malley & Shepherd, 1976). Billing & Black (1971) demonstrated a significant rise in the microsomal cytochrome P-450 content in biopsies of subjects treated with phenobarbitone for a week before abdominal surgery, and Remmer, Schoene, Fleischmann & Held (1973) showed increased activities of drug-metabolizing enzymes in liver biopsy of a female epileptic treated with phenytoin and phenobarbitone.…”

Section: Introductionmentioning

confidence: 96%

Drug metabolism in epileptics: in vivo and in vitro correlations.

Ea¹,

Pelkonen²,

Ahokas³

et al. 1978

I The effect of inducing drug therapy on the relationship between in vitro (cytochrome P-450 content) and in vivo (antipyrine kinetics) was investigated by comparing eleven consecutively treated epileptics with two groups of controls, eleven subjects with normal liver histology and eleven disease matched non-epileptics, all underwent diagnostic liver biopsy. 2 The epileptics had significantly higher cytochrome P-450 level in biopsies and they also metabolized antipyrine taster than the controls. 3 Decrease in antipyrine half-life in epileptics was related with alterations in liver histology, whereas the level of cytochrome P-450 was not. 4 There was a linear relationship between these two indices of enzyme induction when regressed on logarithmic data.