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N-in-1 (or cassette) dosing pharmacokinetics (PK) has been used in drug discovery for rapid assessment of PK properties of new chemical entities. However, because of potential for drug-drug interactions this procedure is still controversial. This study was to retrospectively evaluate the N-in-1 dosing approach in drug discovery with an emphasis on the potential for drug-drug interactions. The systemic clearance, volume of distribution, oral bioavailability, and renal excretion of the 31 lead compounds in rats, dogs or chimpanzees were significantly correlated between the N-in-1 dosing and discrete studies with r values of 0.69, 0.91, 0.53, and 0.83 (p < 0.005 for all), respectively. PK parameters for 11 quality control compounds which were involved in 194 N-in-1 studies for screening approximately 1000 compounds had coefficient of variations of less than 70%. The intrinsic microsomal clearances generated from the N-in-1 and discrete incubations were nearly identical (r = 0.97, p < 0.0001). The intrinsic clearances of quality control compound from the N-in-1 incubations were consistent with its discrete CL(int) estimate (cv: 5.4%). Therefore, N-in-1 dosing is a useful approach in drug discovery to quickly obtain initial PK estimates. Potential drug-drug interactions that result in confounding PK estimates do not occur as frequently as expected.

The effects of precocene II (6,7-dimethoxy-2,2-dimethylchromene) on the kidney were examined histopathologically. Marked changes were observed in the proximal convoluted tubules, collecting tubules, and glomeruli. These changes included congestion of blood in the capillaries of the glomeruli, tubular cell degeneration, and tubular cell regeneration. In addition, blood urea nitrogen levels were elevated in precocene II-treated animals. The results indicate that precocene II is nephrotoxic in the male Sprague-Dawley rat.

The metabolic fate of precocene II (6,7-dimethoxy-2,2-dimethyl-2H-benzo[b]pyran), a potent anti-juvenile hormone, was examined in male Sprague-Dawley rats. When a single intraperitoneal dose of [3H]precocene II was administered, approximately 34% of the administered dose was excreted within the first 24 h. Examination of the various urinary metabolites indicated that precocene II is metabolized to a stereoisomeric cis/trans mixture of the 3,4-dihydroxy-3,4-dihydroprecocene II. In addition, a mercapturic acid derivative of precocene II was tentatively identified. Thus, it is postulated that a highly reactive 3,4-epoxide intermediate is generated in vivo by the rat during oxidative metabolism.