Drug Metabolism and Variability
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《新英格兰医药杂志》
To the Editor: In his review, Wilkinson (May 26 issue)1 mentions grapefruit juice among inducers or inhibitors of various cytochrome P-450 enzymes. Another nonpharmaceutical interaction may be equally important, because of its constant occurrence in users — tobacco. Smoking induces CYP1A2 activity,2 possibly causing a reduced effect of its substrates (e.g., estradiol). Among postmenopausal women receiving 1 or 2 mg daily of oral estrogen, we found that the serum estradiol level in smokers was half that in nonsmokers.3,4 The effect was manifested by about a 50 percent reduction in breast tenderness in smokers.5 Whereas smokers being treated with 1 mg of estradiol had a higher serum level of follicle-stimulating hormone than nonsmokers, no difference was seen in women treated with 2 mg of estradiol.4 Furthermore, smokers who were treated with 1 mg of estradiol had smaller increases in bone mineral density than did nonsmokers. In contrast, there was no difference in bone mineral density between smokers and nonsmokers who were treated with 2 mg of estradiol. Thus, smoking may affect drugs metabolized by CYP1A2, with various consequences on target organs (Table 1).
Table 1. The Qualitative Influence of Smoking during Estrogen Therapy among Postmenopausal Women.
Nina H. Bjarnason, M.D., D.M.Sc.
Rigshospitalet
DK-2200 N Copenhagen, Denmark
nina.bjarnason@rh.dk
References
Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med 2005;352:2211-2221.
Drug interactions. (Accessed August 11, 2005, at http://www.drug-interactions.com.)
Jensen J, Christiansen C, R?dbro P. Cigarette smoking, serum estrogens, and bone loss during hormone-replacement therapy early after menopause. N Engl J Med 1985;313:973-975.
Bjarnason NH, Christiansen C. The influence of thinness and smoking on bone loss and response to hormone replacement therapy in early postmenopausal women. J Clin Endocrinol Metab 2000;85:590-596.
Bjarnason NH, J?rgensen C, Kremmer H, Alexandersen P, Christiansen C. Smoking reduces breast tenderness during oral estrogen-progestogen therapy. Climacteric 2004;7:390-396.
Dr. Wilkinson replies: It is well established that cigarette smoking may lead to the induction of drug metabolism and reduced effects when the usual dosages of certain drugs are administered.1 This effect occurs through a mechanism involving the polycyclic aromatic hydrocarbons inhaled in tobacco smoke and the hepatic aryl hydrocarbon receptor, leading to transcriptional up-regulation of CYP1A2.2 Other environmental factors can also induce CYP1A2, including the ingestion of cruciferous vegetables and charcoal-broiled meat.3 Moreover, CYP1A2 may be inhibited by commonly used drugs, including fluvoxamine, most fluoroquinolones, and oral contraceptives.4 However, the number of drugs with which such interactions are clinically important (estradiol, theophylline, clozapine, olanzapine, and tacrine) is relatively small. Dr. Bjarnason's comment, therefore, further emphasizes that drug metabolism and responsiveness may vary markedly among patients, often for reasons that are not immediately apparent to the prescriber. Consequently, drug dosages need to be individualized to each patient and responses routinely monitored for unexpected changes.
Grant R. Wilkinson, Ph.D., D.Sc.
Vanderbilt University
Nashville, TN 37232
grant.wilkinson@vanderbilt.edu
References
Zevin S, Benowitz NL. Drug interactions with tobacco smoking: an update. Clin Pharmacokinet 1999;36:425-438.
Ma Q, Lu AY. Origins of individual variability in P4501A induction. Chem Res Toxicol 2003;16:249-260.
Harris RZ, Jang GR, Tsunoda S. Dietary effects on drug metabolism and transport. Clin Pharmacokinet 2003;42:1071-1088.
Drug interactions. (Accessed August 11, 2005, at http://www.drug-interactions.com.)
Table 1. The Qualitative Influence of Smoking during Estrogen Therapy among Postmenopausal Women.
Nina H. Bjarnason, M.D., D.M.Sc.
Rigshospitalet
DK-2200 N Copenhagen, Denmark
nina.bjarnason@rh.dk
References
Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med 2005;352:2211-2221.
Drug interactions. (Accessed August 11, 2005, at http://www.drug-interactions.com.)
Jensen J, Christiansen C, R?dbro P. Cigarette smoking, serum estrogens, and bone loss during hormone-replacement therapy early after menopause. N Engl J Med 1985;313:973-975.
Bjarnason NH, Christiansen C. The influence of thinness and smoking on bone loss and response to hormone replacement therapy in early postmenopausal women. J Clin Endocrinol Metab 2000;85:590-596.
Bjarnason NH, J?rgensen C, Kremmer H, Alexandersen P, Christiansen C. Smoking reduces breast tenderness during oral estrogen-progestogen therapy. Climacteric 2004;7:390-396.
Dr. Wilkinson replies: It is well established that cigarette smoking may lead to the induction of drug metabolism and reduced effects when the usual dosages of certain drugs are administered.1 This effect occurs through a mechanism involving the polycyclic aromatic hydrocarbons inhaled in tobacco smoke and the hepatic aryl hydrocarbon receptor, leading to transcriptional up-regulation of CYP1A2.2 Other environmental factors can also induce CYP1A2, including the ingestion of cruciferous vegetables and charcoal-broiled meat.3 Moreover, CYP1A2 may be inhibited by commonly used drugs, including fluvoxamine, most fluoroquinolones, and oral contraceptives.4 However, the number of drugs with which such interactions are clinically important (estradiol, theophylline, clozapine, olanzapine, and tacrine) is relatively small. Dr. Bjarnason's comment, therefore, further emphasizes that drug metabolism and responsiveness may vary markedly among patients, often for reasons that are not immediately apparent to the prescriber. Consequently, drug dosages need to be individualized to each patient and responses routinely monitored for unexpected changes.
Grant R. Wilkinson, Ph.D., D.Sc.
Vanderbilt University
Nashville, TN 37232
grant.wilkinson@vanderbilt.edu
References
Zevin S, Benowitz NL. Drug interactions with tobacco smoking: an update. Clin Pharmacokinet 1999;36:425-438.
Ma Q, Lu AY. Origins of individual variability in P4501A induction. Chem Res Toxicol 2003;16:249-260.
Harris RZ, Jang GR, Tsunoda S. Dietary effects on drug metabolism and transport. Clin Pharmacokinet 2003;42:1071-1088.
Drug interactions. (Accessed August 11, 2005, at http://www.drug-interactions.com.)