Teratogenicity of Antiepileptic Drug Combinations with Special Emphasis on Epoxidation (of Carbamazepine)

Abstract

A higher rate of congenital anomalies has been found after prenatal exposure to some combinations of antiepileptic drugs than to the separate drugs. In an earlier study a rate of 58% congenital anomalies was found among infants exposed to carbamazepine plus phenobarbitone plus valproate. In this study an attempt was made to determine whether this specific combination of drugs has teratogenic activity due to metabolic interaction. The epidemiological data were analyzed further. The high rate of congenital anomalies after prenatal exposure to this combination could not be explained by the effects of one or two of these drugs only, nor by additional exposure to phenytoin. Assuming that metabolic interaction in the arene oxide pathway resulting in accumulation of epoxide intermediates of antiepileptic drugs could be responsible for teratogenesis, the ratio of carbamazepine to carbamazepine-10, 11-epoxide concentrations in serum was determined in adult patients with epilepsy who were treated with carbamazepine only and with different combinations of phenobarbitone, valproate, and/or phenytoin. For carbamazepine monotherapy the mean ratio was 8.19. For all combinations lower ratios were found, indicating accumulation of carbamazepine-10,11-epoxide. The combination of carbamazepine, phenobarbitone, valproate, and phenytoin showed the lowest ratio (1.94), followed by carbamazepine, valproate, and phenytoin and by carbamazepine, phenobarbitone, and valproate (2.81 and 3.18, respectively). These results give rise to the question of whether the combination of carbamazepine, phenobarbitone, valproate, and/or phenytoin has teratogenic activity by accumulation of carbamazepine-10,11-epoxide or other epoxide intermediates, and stress the need to take metabolic interactions into account when investigating the teratogenic activity of antiepileptic drugs.

Blood Levels of Trace Elements, Electrolytes, and Oxidative Stress/Antioxidant Systems in Epileptic Patients

“…In addition, Many conventional AEDs are metabolized to generate reactive metabolites with capability of covalent binding to macromolecules (65).…”

Unilateral multicystic dysplastic kidney in infants exposed to antiepileptic drugs during pregnancy

“…Lindhout et al [12] proposed a reduced activity of epoxide hydrolase, which is involved in the detoxification of epoxides produced in CBZ catabolism. There could be genetic differences in the prevalence of people with low activity of epoxide hydrolase, which may explain the different rates of CBZ-induced congenital anomalies.…”

Antiepileptic Drugs and Pregnancy Outcomes

“…The results of the study on Swiss-Vancouver (SWV) mice indicated that similar to phenytoin, CBZ could be biotransformed to a reactive teratogenic metabolite that might be responsible for the observed fetotoxicity [Finnell et al, 1995]. The primary pathway of metabolism for CBZ involves the oxidative formation of carbamazepine-10, 11-epoxide, which is thought to be responsible for the teratogenicity of the parent drug [Lindhout et al, 1984]. This was confirmed in a study on pregnant mice where carbamazepine-10, 11-epoxide treatment significantly increased the incidence of malformations in foetuses [Bennett et al, 1996;Tecoma, 1999].…”