Anticonvulsant-induced aplastic anemia: increased susceptibility to toxic drug metabolites in vitro

Abstract

A 53-yr-old man sequentially developed aplastic anemia from phenytoin and carbamazepine. Both compounds undergo metabolism to potentially toxic arene oxide intermediates. We tested the hypothesis that the patient's adverse reactions were due to a defect in detoxification of such metabolites by challenging his peripheral lymphocytes with drug metabolites generated by a murine hepatic microsomal system in vitro. The patient's cell viability was normal in the absence of drugs. However, his cells showed greater toxicity from both phenytoin and carbamazepine metabolites than did controls. Toxicity was dependent on microsomes and NADPH. Intermediate toxicity was noted in cells from the patient's mother. The results provide the first evidence for a role of arene oxide drug metabolites in aplastic anemia in humans and suggest that enhanced susceptibility to toxicity may be based on an inherited abnormality in metabolite detoxification.

Carbamazepine Dose Requirements During Stiripentol Therapy: Influence of Cytochrome P‐450 Inhibition Stiripentol

“…Perhaps more significant, the decreased CBZElCBZ plasma ratio suggests that STP may likewise decrease in vivo exposure to chemically reactive epoxide metabolites (arene oxides) of concurrently administered drugs. Arene oxide metabolites have been implicated as a cause of the infrequent but serious toxicities associated with AEDs, such as teratogenicity (Lindhout et al,I984), hepatitis (Spielberg et al, 1981), and blood dyscrasias (Gerson et al, 1983). The most notable AEDrelated toxicity attributed to an arene oxide metabolite is the teratogenic effect of phenytoin (fetal hydantoin syndrome) (Strickler et al, 1985).…”

Possible Atypical Cross‐Sensitivity between Phenytoin and Carbamazepine in the Anticonvulsant Hypersensitivity Syndrome

“…4 Hematologic abnormalities occur in more than 50% of patients and can include leukocytosis, eosinophilia, atypical lymphocytosis, and, rarely, blood dyscrasias such as thrombocytopenia, leukopenia, Coomb' s-negative hemolytic anemia, and aplastic anemia. 2,[10][11][12][13] Other manifestations of AHS that commonly occur are hepatitis, hepatomegaly, splenomegaly, periorbital or facial edema, conjunctivitis, pharyngitis, and the appearance of a "strawberry tongue." 2,8,[14][15][16] Less frequently, myopathy, rhabdomyolysis, interstitial nephritis, and pneumonitis have been reported.…”

Evolving ways that drug therapy is individualized

“…The early study of Dameshek and Colmes 2 presented data indicating that these were "idiosyncratic" or "allergic" reactions to aminopyrine. Spielberg et al [29][30][31][32][33] have carried out a series of studies on cells from patients with these allergic or hypersensitivity reactions to medications. They have found that reactive oxidation products of these drugs are essential for the toxicity to occur, that cells from parents of patients with this kind of toxicity are more susceptible to drug-induced cell death than cells from control subjects, and that pathways of drug metabolism that compete with the oxidation pathway, such as N-acetylation of a sulfonamide, affect the sensitivity of a person to this type of idiosyncratic drug toxicity.…”