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

Abstract

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.

Lack of enzyme induction with oxcarbazepine (600 mg daily) in healthy subjects.

“…devoid of any auto-inducing effects, as the half-life of oncentrations of 10-OH-CZ in eight male subjects the active metabolite remained unchanged after 2 xcarbazepine 300 mg twice daily weeks' administration, a time period sufficient for nearmaximum induction by equivalent doses of CBZ (Mikati et al, 1989;Rapeport et al, 1983). The confidence interval 'excludes' a fall of 26% as opposed to previously demonstrated reductions in CBZ half-life on chronic therapy of 38% (Rapeport et al, 1983) and 40% (Larkin et al, 1989a).…”

“…The confidence interval 'excludes' a fall of 26% as opposed to previously demonstrated reductions in CBZ half-life on chronic therapy of 38% (Rapeport et al, 1983) and 40% (Larkin et al, 1989a). The standard markers of cytochrome P450 induction -antipyrine metabolism and 6-,-hydroxycortisol excretion (Park, 1982;Rimmer et al, 1986;Roots et al, 1979) -were also unaffected by OXC therapy.…”

“…The standard markers of cytochrome P450 induction -antipyrine metabolism and 6-,-hydroxycortisol excretion (Park, 1982;Rimmer et al, 1986;Roots et al, 1979) -were also unaffected by OXC therapy. Confidence intervals were against the likelihood of a reduction of 25% in antipyrine half-life [previously shown falls with CBZ -33% (Connell et al, 1984), 35% (Larkin et al, 1989a)], an increase of 33% in antipyrine clearance [CBZ -39% (Connell et al, 1984)], and a rise in 6-,B-hydroxycortisol excretion of 79% [CBZ -178% (Rapeport et al, 1983)]. These differences are illustrated graphically in Figure 6, which also compares changes in sex hormone and binding protein concentrations.…”

“…Hyponatraemia, on the other hand, may be as common with OXC as with CBZ (Nielson et al, 1988 An important drawback to the clinical use of CBZ is its ability to induce hepatic monooxygenase enzymes (Wagner & Schmid, 1987). Chronic dosing shortens its elimination half-life (Eichelbaum et al, 1975;Rapeport et al, 1983) thus reducing steady-state concentrations which occasionally results in breakthrough seizures (Macphee & Brodie, 1985). The extent of this process contributes to the three-fold variation in trough and peak plasma CBZ concentrations in patients receiving the same daily dose (Macphee et al, 1987).…”

“…The present study was designed to investigate enzyme induction with OXC, in particular its effect on serum concentrations of the active metabolite, 10-OH-CZ, and its influence on other endogenous and exogenous substances metabolised by inducible pathways and previously shown to be affected by treatment with equivalent doses of CBZ (Connell et al, 1984;Rapeport et al, 1983 0,1,2,3,4,6,8,10,12,24,32,48,56,72 and 96 h later for measurement of serum OXC, its major metabolite 10-OH-CZ and a further metabolic product 10, 11-dihydrotrans-10, 11-dihydroxy-carbamazepine (transdiol).…”