THALIDOMIDE INDUCED NEUROPATHY AND GENETIC-DIFFERENCES IN DRUG-METABOLISM

A pharmacogenetic predisposition to thalidomide-induced neuropathy has been investigated. Differences of drug metabolism were examined in 16 patients with severe orogenital ulceration, who were treated with tha lidomide (less than or equal to 200 mg/day) for 0.3-5.0 years. Eight h ad evidence of early peripheral neuropathy according to nerve conducti on studies. Rates of C-hydroxylation, N-acetylation, and conjugation r eactions with sulphate, glucuronide and glycine, were tested with the probe compounds debrisoquine, sulphadimidine, paracetamol and aspirin, respectively. Urinary drug metabolites were analysed by high pressure liquid chromatography. Results were compared with 16 healthy age- and sex-matched volunteers. Of the patients 6.25 % and 13.3 % of the cont rols had a poor Debrisoquine Hydroxylator Ratio (DMR); none of the pat ients with neuropathy had a poor DMR as compared to 12.5 % without neu ropathy. Of the patients 40.0 % and 35.7 % of the controls were slow a cetylators; 28.6 % with neuropathy were slow acetylators as opposed to 50 % without neuropathy. Similarly, there were no significant differe nces in rates of conjugation between groups. All unaffected patients w ere active smokers, whereas only two of those with neuropathy smoked. Cumulative dose or duration of therapy were unrelated to risk of neuro pathy. In conclusion, changes of nerve conductivity are a frequent and unpredictable adverse effect of thalidomide (less than or equal to 20 0 mg/day), although smoking may have a protective action against their development. Nerve conduction studies are required before and during treatment, irrespective of the prescribed dose.