The plasma clearance (CL) of lorazepam (LOR), a pharmacologic“probe” for evaluating drug metabolism by UDP-glucuronyltransferase (GT), has been shown to be markedly (ie. 2.2 fold) greater in patients with moderate-severe cystic fibrosis (CF) as compared to healthy controls (Kearns GL, et al. J Pediatr 1990;117:972·9). In a recent study (Clin Pharmacol Ther, in press, 1995), we also found that the CL of LOR following a 0.03 mg/kg IV dose in 15 patients with CF (8.7·19.3 yr) who had minimal disease involvement (ie. 1.7 ± 0.4 ml/min/kg) was significantly greater than observed in 14, healthy, age· (8.9·18.9 yr) and gender-matched controls (CL = 1.2 ± 0.5 ml/min/kg; p = 0.01). Given no difference in LOR VDss, it became essential to determine whether the increase in the CL of LOR reflected increased GT activity in CF per se. Methods: 24-hr quantitative urine collections were obtained from the aforementioned subjects and were analyzed by HPLC for free LOR and indirectly (ie. after glucuronidase treatment), for LOR-glucuronide (LOR-gluc). Results: Evaluable urine collections were available from 14/15 patients with CF and 11/15 controls. Free LOR was not detected in any of the specimens. The total amount of LOR-gluc excreted (Ae) and the fraction of the dose eliminated as LOR-gluc (Fel) for CF vs. controls were as follows: Ae = 195.6± 107.4 μg (or 4.5 ± 2.4 μg/kg) vs. 263.4 ± 220.6μg (or 4.4 ± 3.3 μg/kg) [p > 0.05] and Fel = 15.0 ± 8.1% vs. 14.6 ± 11.1% [p > 0.05]. Conclusions: The increased CL of LOR in CF is apparently not a result of an increase in GT activity as assessed by the urinary excretion of LOR-gluc. Given the proven adequacy of LOR as a “probe” for GT, the observed differences in the CL of LOR in CF vs. controls may result from previously unrecognized alterations in other pathways for LOR metabolism (eg., hydroxylation or the formation of quinazolinine derivatives) in this disease. (supported by CF Foundation grant #A028 0·2)