The contribution of the active metabolites to the tolerance developing to diazepam in man: relationship to bioassayed serum benzodiazepine levels.

Seven healthy students cooperated in this study. They underwent four experimental periods at one-month intervals, each period comprising a single-dose test with diazepam (D) 15 mg, oxazepam (OX) 45 mg, nordiazepam (ND) 15 mg or placebo (given double-blind in randomized order) on day 1, followed by maintenance with respective drug for 7 days, and a retest with D 15 mg on day 8. Thus, psychomotor responses to D 15 mg were measured after one-week treatment with D 5 mg, OX 15 mg, ND 5 mg, or placebo, all taken twice daily. Serum samples were taken at each session day before and 2.5 hr after the drug intake for bioassay of serum benzodiazepine (BZ) levels against commensurable diazepam standard. On day 1, a single dose of OX 45 mg resulted in fourfold concentrations of serum BZ levels in comparison with the results of the doses D 15 mg and ND 15 mg. Psychomotor skills were also most impaired by oxazepam. ND 15 mg was less effective than D 15 mg, irrespective of the same serum BZ levels. One-week of treatment with D and OX seemed to diminish most responses to D, despite increased BZ effects on these functions. Pretreatment with ND reduced the subjective sedative effects of D. Our results support the view that the rate of development of tolerance to BZs is task-dependent. Tolerance developed mostly to the complex tests subject to learning while Maddox wing test (reflecting the degree of muscle relaxation) was resistant. ND, the main metabolite of D, plays little part in the tolerance that developed to D.