LETTERS TO THE EDITOR Deficient C-oxidation of nicotine continued To the Editor: Nakajima et all described a person with deficient metabo- lism of nicotine to cotinine whose abnormal metabolism was explained by a CYP2A6 gene deletion. The authors referred to an earlier report of Benowitz et al* that described another person with deficient metabolism of nicotine to cotinine, and they suggested that the same gene defect may be responsible. We have subsequently performed a genetic analysis on DNA from the subject in the report by Benowitz et aL2 as well as on another person who was found to have deficient metabolism of nicotine to cotinine. Genotyping for the CYP2A6*2 and CYP2A6*4 (gene deletion) alleles was done with use of allele-specific assays as described previously.3,4 The previously published case was found to have a homozy- gous CYP2A6*2 genotype. The second deficient metabolizer had neither the CYP2A6*2 point mutation allele nor the CYP2A6*4 gene deletion. Work is ongoing to try to deter- mine the nature of the CYP2A6 gene defect in the latter indi- vidual. We conclude that deficient metabolism of nicotine can result from being homozygous for 1 of several CYP2A6 alleles with gene mutations. Neal L. Benowitz, MD Chandi Grifin, MA University of California, San Francisco San Francisco, Calif Rachel Tyndale, PhD University of Toronto Toronto, Ontario, Canada References 1. Nakajima M, Yamagishi S, Yarnamoto H, Yamamoto T, Kuriowa Y, Yokoi T. Deficient cotinine formation from nicotine is attrib- uted to the whole deletion of the CYP2A6 gene in humans. Clin Pharmacol Ther 2000;67:57-69. 2. Benowitz N, Jacob P, Sachs D. Deficient C-oxidation of nico- tine. Clin Pharmacol Ther 1995;57:590-4. 3. Oscarson M, Gullsten H, Rautio A, Bernal ML, Sinues B, Dahl ML, et al. Genotyping of human cytochrome P450 2A6 (CYP2A6), a nicotine C-oxidase. FEBS Lett 1998;438:201-5. 4. Oscarson M, McLellan R, Gullsten H, Yue QY, Lang MA, Bemal ML, et al. Characterization and PCR-based detection of a CYP2A6 gene deletion found at a high frequency in a Chinese population. FEBS Lett 1999;448:105-10. 13lW120252 doi:l0.1067/mcp.2001.120252 QTc prolongation and drugs To the Editor: We commend Abernethy et all for their well-designed study of the potential cardiotoxic effects of combining nefa- zodone and nonsedating antihistamines. There are several points that we would like to clarify. The authors hypothesized that nefazodone (as a cytochrome P4503A substrate) in combination with either loratadine (partially metabolized by CYP3A) or terfenadine (largely metabolized by CYP3A) would lead to significant prolongation in the QTc intervals of subjects. This is not only biologically plausible but was both epidemiologically and anecdotally supported before the experiment.2,3 In fact, ter- fenadine was voluntarily withdrawn from public consump- tion long before the publication of this study as a result of these exact concerns. It is not clear whether these data were generated before the deleterious effects of these drugs were well known. Given the potential morbidity and mortality rates associated with QTc prolongation, we question how the authors and their institutional review board justified the absence of basic safety precautions in their study design. The subjects were outpatients and received only occasional elec- trocardiographic monitoring. Two subjects were withdrawn from the study because of symptoms that included dizziness, nausea, and vomiting. We are told that physical findings were unchanged from baseline, but we are not given their specific electrocardiographic data. It is not difficult to believe that these symptoms could have been the result of cardiac con- duction abnormalities. It is also not stated in the Methods section whether sub- jects were required to refrain from the use of other medica- tions, over-the-counter preparations, or foods that contain P450-inhibiting agents, such as grapefruit juice, that might have interfered with various P4.50 enzyme systems.4,5 Although further valuable information about the potential cardiotoxic effects of loratadine could be derived from a sim- ilar study of loratadine and nefazodone treatment of a longer duration, we caution these and other investigators to include measures to ensure subject safety. William Henderson, MD Vancouver Hospital and Health Sciences Centre Vancouven British Columbia, Canada Jason Chu, MD Robert Ho#man, MD New York City Poison Control Center New York. NY CLINICAL PHARMACOLOGY & THERAPEUTICS DECEMBER 2001 567