Correspondence

Drug Metabolism and Variability

N Engl J Med 2005; 353:955-956September 1, 2005

Article

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 1Table 1The 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

5 References

1. 1

   Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med 2005;352:2211-2221
   Full Text | Web of Science | Medline

2. 2

   Drug interactions. (Accessed August 11, 2005, at http://www.drug-interactions.com.)
   

3. 3

   Jensen J, Christiansen C, Rodbro P. Cigarette smoking, serum estrogens, and bone loss during hormone-replacement therapy early after menopause. N Engl J Med 1985;313:973-975
   Full Text | Web of Science | Medline

4. 4

   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
   CrossRef | Web of Science | Medline

5. 5

   Bjarnason NH, Jorgensen C, Kremmer H, Alexandersen P, Christiansen C. Smoking reduces breast tenderness during oral estrogen-progestogen therapy. Climacteric 2004;7:390-396
   CrossRef | Web of Science | Medline

Author/Editor Response

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

4 References

1. 1

   Zevin S, Benowitz NL. Drug interactions with tobacco smoking: an update. Clin Pharmacokinet 1999;36:425-438
   CrossRef | Web of Science | Medline

2. 2

   Ma Q, Lu AY. Origins of individual variability in P4501A induction. Chem Res Toxicol 2003;16:249-260
   CrossRef | Web of Science | Medline

3. 3

   Harris RZ, Jang GR, Tsunoda S. Dietary effects on drug metabolism and transport. Clin Pharmacokinet 2003;42:1071-1088
   CrossRef | Web of Science | Medline

4. 4

   Drug interactions. (Accessed August 11, 2005, at http://www.drug-interactions.com.)
   

Citing Articles (3)

Citing Articles

1. 1

   N. H. Bjarnason, H. L. Jørgensen, C. Christiansen. (2011) Acute and long-term estradiol kinetics in smoking postmenopausal women. Climacteric1-6
   CrossRef

2. 2

   Anna M. McDivit, Gail A. Greendale, Frank Z. Stanczyk, Mei-Hua Huang. (2008) Effects of alcohol and cigarette smoking on change in serum estrone levels in postmenopausal women randomly assigned to fixed doses of conjugated equine estrogens with or without a progestin. Menopause 15:2, 382-385
   CrossRef

3. 3

   Sheila A Doggrell. (2005) Recent findings with docetaxel in postoperative treatment for breast cancer. Expert Opinion on Pharmacotherapy 6:16, 2903-2906
   CrossRef