Phenytoin teratogenicity

Tiboni GM, Giampietro F, Angelucci S, Moio P, Bellati U, Di Illio C. Additional investigation on the potentiation of phenytoin teratogenicity by fluconazole. Toxicol Lett 2003 145 219-29. 

Winn LM, Wells PG. Phenytoin-initiated DNA oxidation in murine embryo culture, and embryo protection by the antioxidative enzymes superoxide dismutase and catalase Evidence for reactive oxygen species-mediated DNA oxidation in the molecular mechanism of phenytoin teratogenicity. Mol Pharmacol 1995 48 112-20. 

A final remarkable feature of teratogenesis is the dramatic species- and strain-dependent variability in susceptibility for some xenobiotics. For example, some strains of mice are sensitive to phenytoin teratogenicity, while other strains are resistant. In the case of thalidomide, primates (including humans) and rabbits are sensitive, while all rodent (mice and rats) strains tested are resistant. These differences must be considered in the design and interpretation of data from animal studies when directed towards an evaluation of human risk. 

Diphenylhdantoin (phenytoin) GM (PE) 1 Widely used. Hyperplasia of gums. Anti-folate. Teratogenic. Ineffective in PM (20-80)... 

Phenobarbital, carbamazepine, and phenytoin potentially reduce efficacy of OCs, and many anticonvulsants are known teratogens. The use of condoms in conjunction with high-estrogen OCs or intrauterine devices (IUDs) may be considered for women taking these drugs. 

Another location with high prostaglandin-synthase activity and low P450 levels is the fetus, and it has been proposed that the teratogenicities of benzo[a]pyrene and phenytoin are due to cyclooxygenase-mediated bioactivation of these agents (45,46). 

Parman T, Chen G, Wells PG. Free radical intermediates of phenytoin and related teratogens. Prostaglandin H synthase-catalyzed bioactivation, electron paramagnetic resonance spectrometry, and photochemical product analysis. J Biol Chem 1998 273(39) 25079-25088. 

Habert, R. and Picon, R. (1984). Testosterone, dihytrostestosterone and estradiol-17/ levels in maternal and fetal plasma and in fetal testes in the rat. J. Steroid Biochem. 21 183-198. Hansen, D.K. and Hodes, M.E. (1983). Comparative teratogenicity of phenytoin among several inbred strains of mice. Teratology 28 175-179. 

There is evidence that phenytoin is teratogenic in humans, but the mechanism is not clear. However, it is known that phenytoin can produce a folate deficiency, and folate deficiency is associated with teratogenesis. 

Sullivan, F.M. and McElhatton, P.R. (1975) Teratogenic activity of the antiepileptic drugs phenobarbital, phenytoin, and primidone in mice. Toxicol Appl Pharmacol 24 271—282. 

Mebendazole is teratogenic in animals and therefore contraindicated in pregnancy. It should be used with caution in children younger than 2 years of age because of limited experience and rare reports of convulsions in this age group. Plasma levels may be decreased by concomitant use of carbamazepine or phenytoin and increased by cimetidine. Mebendazole should be used with caution in patients with cirrhosis. 

As with carbamazepine, phenytoin also causes idiosyncratic toxic effects, including hematological and connective tissue toxicities, hepatotoxicity, and teratogenicity (89). Although some of these toxicities have been hypothesized to be caused by P450 oxidative metabolism (92,93) or peroxidase-mediated reactions (94,95), mechanisms for these toxic effects in humans are unknown. 

Adverse effects These are primarily related to CNS and Gl disturbances. They include impaired concentration, dizziness, ataxia, diplopia, somnolence, nervousness, and confusion, as well as nausea and weight loss. Renal stones have been reported in 1.5 percent of patients. Topiramate is teratogenic in animals, and should be avoided during pregnancy. Inducers of drug metabolism such as phenytoin and carbamazepine decrease topiramate serum concentrations by approximately 50 percent. Topiramate decreases ethinyl estradiol concentrations of oral contraceptive preparations, and individuals should supplement the amount of ethinyl estradiol. 

Martz et al. (109) used a mouse model to provide the first evidence that the epoxide metabolite of phenytoin might be similarly implicated in mediating teratogenic reactions to this drug. Pregnant mice were treated... 

Drugs known to be teratogenic include cytotoxics, warfarin, alcohol, lithium, methotrexate, phenytoin, valproate, ACE inhibitors and isotretinoin. Selective interference can produce characteristic anatomical abnormalities, and the phocomelia (flipper-Uke) limb defect was one factor that caused thalidomide to be so readily recognised. (For an account of thalidomide see p. 81.)... 

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