Letters to the Editors

Abstract

indicative of renal and hepatic function. Alcohol, caffeine Effects of ketoconazole on the erythromycin and grapefruit-derived products were not permitted for breath test and the dapsone recovery ratio 24 h prior to and during the study period, and all of the Cytochrome P4503A (CYP3A)-a term used to indicate subjects were non-smokers. Each subject received placebo the collective metabolic activity of CYP3A4 and CYP3A5 followed by 300 mg ketoconazole daily, each for 7 days. in adult humans-is the most abundant of the hepatic After administration of the final dose in each study arm, CYP isoforms [1]. Because of this and its broad substrate the ERMBT was performed in the fasted state following specificity, CYP3A is involved to a varying extent in the rapid intravenous injection of 3 mCi [ 14 C-N-methyl]-metabolism of a large number of drugs [1]. Moreover, its erythromycin (DuPont New England Nuclear, Boston, localization in both the intestinal epithelium and liver MA), collection of expired air over the subsequent makes it important in the often marked oral first-pass 60 min, and measurement of 14 CO 2 as previously metabolism of many of its substrates [2]. Additionally, described [7]. One hour later, 100 mg dapsone ( Jacobus CYP3A's unimodal frequency distribution exhibits conPharmaceutical Co., Inc., Princeton, NJ) was orally siderable (5-to 10-fold) variability in activity that can be administered and urine collected for the subsequent 8 h, readily altered by inducers and inhibitors [1]. Accordingly, using ascorbic acid (1 g ) as preservative. Dapsone and its a means by which CYP3A activity and its modulation in N-hydroxy metabolite were determined by an h.p.l.c.-individuals could be readily assessed in vivo would be of based procedure and the DPRR (amount of dapsone value. The erythromycin breath test (ERMBT), based on hydroxylamine excreted/amount of dapsone and its the CYP3A-mediated N-demethylation of radiolabeled hydroxylamine excreted) estimated as described previously erythromycin, has been developed and used in several [14]. Between treatment differences in the indices were clinical studies for this purpose [3][4][5][6][7][8][9]. However, this test analyzed by a paired Student's t-test with P=0.05 being has several limitations, not the least of which is that it only taken as the minimal level of significance. measures hepatic metabolism [4, 5, 10, 11] and then only Seven days of ketoconazole administration reduced the that mediated by CYP3A4 [12]. Accordingly, intestinal ERMBT value markedly by 76% (2.23±0.5 vs 0.56±0.2% metabolism following oral administration and any