Lymphocyte microsomal epoxide hydrolase in patients on carbamazepine therapy.

Abstract

1. In order to determine whether carbamazepine is an inducer of lymphocyte microsomal epoxide hydrolase, the activity of the enzyme has been measured in the lymphocytes of 40 patients on continuous drug therapy using [3H]‐cis stilbene oxide as a substrate. 2. Induction of the cytochrome P450 isoform, CYP3A, has been assessed in the same patients by measurement of the 24 h urinary excretion of 6 beta‐ hydroxycortisol by radioimmunoassay. The urinary concentrations of carbamazepine and its two metabolites, the 10,11‐epoxide and trans‐ dihydrodiol, have also been measured by h.p.l.c. 3. The 24 h urinary 6 beta‐hydroxycortisol excretion in the patients increased with the dose of carbamazepine (r = 0.57, P < 0.001) indicating induction of CYP3A. 4. The total amount of trans‐dihydrodiol excreted in the urine increased with the dose of carbamazepine, and it was the most abundant urinary metabolite in all patients and at all dose‐levels. There was no relationship between the dose of carbamazepine and the diol to epoxide ratio (r = 0.01, NS). 5. Lymphocyte microsomal epoxide hydrolase activity was marginally, but significantly (P = 0.02) higher in the patients (28.4 pmol diol min‐1 mg‐1 protein) than in drug‐free controls (23.4 pmol diol min‐1 mg‐1 protein (95% CI for difference ‐9 to ‐0.8)). 6. The results indicate that at concentrations of carbamazepine which produce marked induction of hepatic CYP3A, an enzyme involved in the metabolism and bioactivation of carbamazepine, there is only a slight increase in lymphocyte microsomal epoxide hydrolase.

Effect of Carbamazepine on the Single Oral Dose Pharmacokinetics of Alprazolam

“…Furthermore, carbamazepine markedly increased the CLoral and shortened the elimination t1/2 of alprazolam. These results indicate that carbamazepine, an inducer of CYP3A4 (Wietholtz et al 1989;Pirmohamed et al 1994), induces the metabolism of al- The values on the table are means Ϯ SD. Abbreviations: Cmax ϭ peak plasma concentration; tmax ϭ time to Cmax; CLoral ϭ apparent oral clearance; Vd ϭ apparent volume of distribution; t1/2 ϭ half-life.…”

“…However, it has been suggested that carbamazepine induces the metabolism of several psychotropic drugs (Arana et al 1986;Backman et al 1996;Otani et al 1996b;1997b) by a not fully characterized enzyme induction. Previous studies have suggested that carbamazepine induces CYP3A4 (Wietholtz et al 1989;Pirmohamed et al 1994;Yue et al 1994), but not CYP1A2 (Wietholtz et al 1989), CYP2D6 (Yue et al 1994) nor UDP-glucuronosyltransferases (Yue et al 1994). Therefore, carbamazepine may decrease plasma concentration of alprazolam by inducing its metabolism.…”

Significant pharmacokinetic interaction between risperidone and carbamazepine: its relationship with CYP2D6 genotypes

“…Carbamazepine increases urinary 6β-hydroxycortisol output (Wietholtz et al 1989;Pirmohamed et al 1994), suggesting that it induces metabolism catalyzed by CYP3A4. However, it does not affect caffeine metabolism (Wietholtz et al 1989) or O-demethylation and glucuronidation of codeine .…”

CYP3A4 and CYP2A6 activities marked by the metabolism of lignocaine and coumarin in patients with liver and kidney diseases and epileptic patients.

“…Since, we presume that these patients had normal hepatic blood flow, it is likely that this observation can be explained by competition between the anticonvulsant agents and lignocaine for CYP3A4, as seen in patients treated with erythromycin and amiodarone [8,28,29]. Nine out of 12 epileptic patients were treated with carbamazepine and epoxidation of this compound is mediated by CYP3A4 [35]. The use of drugs competing for CYP3A4 may delay MEGX production invalidating the MEGX test as an index of decreased liver function.…”