3. Kirchheiner J, Meineke I, Freytag G, Meisel C, Roots I, Brock-möller J. Enantiospecific effects of cytochrome P450 2C9 aminoacid variants on ibuprofen pharmacokinetics and on the inhibitionof cyclooxygenases 1 and 2. Clin Pharmacol Ther 2002;72:62-75.

4. Martinez C, Blanco G, Ladero JM, Garcia-Martin E, Taxonera C,Gamito FG, et al. Genetic predisposition to acute gastrointestinalbleeding after NSAIDs use. Br J Pharmacol 2004;141:205-8.

5. Chan AT, Giovannucci EL, Meyerhardt JA, Schernhammer ES,Curhan GC, Fuchs CS. Long-term use of aspirin and nonsteroidalanti-inflammatory drugs and risk of colorectal cancer. JAMA2005;294:914-23.

6. Ulrich CM, Bigler J, Potter JD. Non-steroidal anti-inflammatorydrugs for cancer prevention: promise, perils and pharmacogenet-ics. Nat Rev Cancer 2006;6:130-40.

doi:10.1016/j.clpt.2006.08.003

Tolerability of �-blockers metabolized viacytochrome P450 2D6 is sex-dependent

To the Editors:Wuttke et al1 observed a predominance of cytochrome

P450 (CYP) 2D6 poor metabolizers (PMs) in patients withserious metoprolol-associated adverse events. Interestingly,18 of their 24 patients were women. Metoprolol is a CYP2D6substrate, and higher plasma concentrations have been dem-onstrated in PMs when compared with extensive metaboliz-ers.2,3 However, other authors did not observe a higher fre-quency of adverse drug reactions (ADRs) in metoprolol-treated hypertensive patients who were PMs for CYP2D6.4

Independent of CYP2D6 genotype, women exhibit signifi-cantly higher metoprolol and propranolol plasma concentra-tions than men.5

Therefore we analyzed data from our longitudinalpopulation-based study with prospective event assessment6 toidentify potential sex differences in ADRs caused by�-blockers during the years 2000 to 2002 (n � 124 cases). Inbrief, all consecutive hospitalizations to departments of inter-nal medicine were evaluated, and suspected drug-relatedcases were documented as described earlier.6 Because thedisposition of metoprolol,2 carvedilol,2 nebivolol,3 and pro-pranolol3 is at least to some extent controlled by the poly-morphic CYP2D6, we grouped these �-blockers as CYP2D6-dependent in contrast to the CYP2D6-independent �-blockersatenolol, sotalol, and bisoprolol.3 The 2 groups were com-pared by use of the Mann-Whitney test and Fisher exact testas appropriate.

The maintenance doses, dose/weight ratios, and number ofdrugs administered (mean, 6.1 � 3.2 in women and 5.6 � 2.8in men) were not different between women and men (Table I).In women and men the most frequently detected ADRs werebradycardia (60.8% versus 60.0%), syncope (10.8% versus12.0%), and hypotension (5.4% versus 6.0%).

The number of ADRs associated with the use of CYP2D6-dependent �-blockers was significantly higher in women (n �46) than in men (n � 18) (P � .006) (Fig 1), whereas thefrequencies for the CYP2D6-independent �-blockers were

not different between men (n � 32) and women (n � 28) (P� .05). Drug interactions between heart rate–lowering drugs(mainly verapamil and digitoxin) and CYP2D6-dependent�-blockers occurred significantly more frequently in womenthan in men, whereas there was no sex difference for inter-actions with CYP2D6-independent �-blockers (P � .015).

The underlying reason for our findings could be subtlepharmacokinetic differences resulting in higher �-blockerplasma levels, which lead in turn to more ADRs, especially incombination with interacting drugs. A preference of prescrib-ing �-blockers to women is unlikely according to data avail-able in Germany, where men more frequently receive pre-scriptions of �-blockers than women.7 Even though theinformation on sex differences in the activity of CYP2D6 anddisposition of �-blockers is still contradictory, the data fromour epidemiologic study confirm a significant sex differencewith regard to the safety of the CYP2D6-dependent�-blockers metoprolol, carvedilol, nebivolol, and proprano-lol. Our observation should encourage further epidemiologicresearch on sex differences with regard to the safety ofCYP2D6 substrates and sex-specific analyses of ADRs inlarge clinical trials with �-blockers, particularly metoprolol.

Petra A. Thürmann, MDSara Haack

Ulrike Werner, PhDJacek Szymanski

Philipp Klee-Institute of Clinical PharmacologyUniversity Witten/Herdecke

Witten, GermanyHELIOS Klinikum Wuppertal

Wuppertal, Germany

metoprolol

carvedilol

nebivolol

propranolol

sotalol

bisoprolol

atenolol

men

women0

5

10

15

20

25

30

CYP2D6-dependent CYP2D6-independent

ADRs(n)

Fig 1. Sex-specific frequency of drug-related hospitalizations(adverse drug reactions [ADRs]) associated with different�-blockers grouped according to their metabolism via CYP2D6.

CLINICAL PHARMACOLOGY & THERAPEUTICS2006;80(5):549-60 Letters to Editor 551

Grit HaaseBernd Drewelow, MD

Institute of Clinical PharmacologyUniversity of Rostock

Rostock, Germany

Ilselore R. Reimann, MDSophien and Hufeland Klinikum

Weimar, GermanyInstitute of Clinical Pharmacology

Friedrich Schiller-University of JenaJena, Germany

Marion Hippius, PhDInstitute of Clinical Pharmacology

Friedrich Schiller-University of JenaJena, Germany

Werner Siegmund, MDKaren May, PhD

Institute of Clinical PharmacologyErnst Moritz Arndt University of Greifswald

Greifswald, Germany

Joerg Hasford, MDInstitute of Biostatistics and Epidemiology

Ludwig-Maximilians-UniversityMunich, Germany

E-mail: pthuermann@wuppertal.helios-kliniken.de

Supported by Bundesinstitut für Arzneimittel und Medizin-produkte (Federal Institute for Drugs and Medical Devices) (Fo2.1-68502-201).

Data presented are part of the doctoral thesis of Sara Haack,University of Witten/Herdecke, Witten, Germany.

None of the authors has any financial relationship to the pharma-ceutical manufacturers of the �-blockers evaluated.

References

1. Wuttke H, Rau T, Heide R, Bergmann K, Bohm M, Weil J, et al.Increased frequency of cytochrome P450 2D6 poor metabolizersamong patients with metoprolol-associated adverse effects. ClinPharmacol Ther 2002;72:429-37.

2. Flockhart D. Cytochrome P450 drug-interaction table. IndianaUniversity School of Medicine Web site. Last updated June 22,2006. Available from: URL:http://www.medicine.iupui.edu/flock-hart/table.htm. Accessed July 13, 2006.

3. Micromedex healthcare series 2006. Available from: URL:www.micromedex.com Accessed July 13, 2006.

4. Fux R, Morike K, Prohmer AM, Delabar U, Schwab M, Schaef-feler E, et al. Impact of CYP2D6 genotype on adverse effectsduring treatment with metoprolol: a prospective clinical study.Clin Pharmacol Ther 2005;78:378-87.

5. Jochmann N, Stangl K, Garbe E, Baumann G, Stangl V. Female-specific aspects in the pharmacotherapy of chronic cardiovasculardiseases. Eur Heart J 2005;26:1585-95.

6. Schneeweiss S, Hasford J, Goettler M, Hoffmann A, RiethlingAK, Avorn J. Admissions caused by adverse drug events tointernal medicine and emergency departments in hospitals: a lon-gitudinal population-based study. Eur J Clin Pharmacol 2002;58:285-91.

7. Pittrow D, Kirch W, Bramlage P, Lehnert H, Höfler M, Unger T,et al. Patterns of antihypertensive drug utilization in primary care.Eur J Clin Pharmacol 2004;60:135-42.

doi:10.1016/j.clpt.2006.08.004

Table I. Demographic data and doses of �-blockers in 124 patients with adverse drug reactions

�-Blocker (No. of women/No.of men)

Age (y) Height (cm)

Women Men Women Men

All (74/50) 75.3 � 10.3 69.4 � 11.6* 159 � 5 174 � 6†CYP2D6-dependent (46/18) 76.0 � 8.4 71.8 � 6.1 160 � 5 172 � 7†

Metoprolol (27/7) 75.8 � 9.7 72.6 � 6.0 158 � 5 172 � 4Carvedilol (7/5) 78.4 � 5.4 73.6 � 5.7 162 � 5 174 � 14Nebivolol (7/4) 75.3 � 8.2 69.3 � 8.5 160 � 7 172 (n � 1)Propranolol (5/2) 74.2 � 3.7 69.5 � 3.5 161 � 4 172 (n � 1)

CYP2D6-independent (28/32) 74.2 � 13.0 68.0 � 13.7 159 � 6 174 � 6†Sotalol (14/15) 75.3 � 6.6 71.9 � 0.2 161 � 5 175 � 7Bisoprolol (12/12) 77.0 � 9.3 63.6 � 17.6 156 � 6 173 � 5Atenolol (2/5) 50.2 � 42.4 67.0 � 13.4 158 � 8 174 � 5

Data are given as mean � SD.*P � .001 for comparison with women by Mann-Whitney test.†P � .0001 for comparison with women by Mann-Whitney test.

CLINICAL PHARMACOLOGY & THERAPEUTICS552 Letters to Editor NOVEMBER 2006

Warfarin dose requirement for patients with bothVKORC1 3673A/A and CYP2C9*3/*3 genotypes

To the Editor:Recently, interindividual variation in the maintenance dose

of warfarin has been accounted for by several genetic factors,including cytochrome P450 (CYP) 2C9 and vitamin K epox-ide reductase complex subunit 1 (VKORC1), according toexcellent articles reported by Aquilante et al1 and Lee et al2

in this journal.We have encountered a 69-year-old female patient (weight,

79.8 kg) with atrial fibrillation whose maintenance dose ofwarfarin was quite low, 0.5 mg/d (international normalizedratio [INR], 1.93; target INR, 1.5-2.0). For that reason, wetried to analyze her genotypes and measure the plasma con-centration of S- and R-warfarin by HPLC3 after receivinginformed consent from her. Surprisingly, we found that she ishomozygous for CYP2C9*3 and for 3673A of VKORC1(VKORC1A/A). In addition, the data of 14 patients werefurther interpreted with regard to the relationship between themaintenance dose of warfarin and their genotypes (Fig 1).Four patients with VKORC1A/G and CYP2C9*1/*1 wereidentified as taking the 4 highest doses among all patients,consistent with several reports.1 The plasma concentration ofS-warfarin (286 ng/mL) in the patient with CYP2C9*3/*3(VKORC1A/A) was rather high compared with that in patientswith CYP2C9*1/*1 and VKORC1A/A (mean [� SD], 140 �50 ng/mL; range, 96-257 ng/mL), although the dose (0.5mg/d) and R-warfarin concentration (132 ng/mL) were thelowest of the patients (mean, 451 � 127 ng/mL; range,214-684 ng/mL). This study was approved by the institutionalethical board of Osaka University, Osaka, Japan.

Patients with both CYP2C9*3/*3 and VKORC1A/A arerare, especially among the white population, becauseVKORC1G/G is the major genotype in white persons.However, these patients should be treated carefully, be-cause they are expected to require the lowest dose ofwarfarin. So far, 2 cases have been reported concerning themaintenance dose of warfarin in patients withCYP2C9*3/*3 in a Japanese population. One patient re-

ceived 0.4 mg/d of warfarin,3 whereas in another patient,identified from a sample of 828 Japanese patients, thesymptoms seemed to be controlled by 2.0 mg/d of warfa-rin.4 The maintenance dose of the second patient wassimilar to the mean dose (2.0 mg/d) for patients withCYP2C9*1/*3 and VKORC1A/A. According to data inwhite subjects,5 those with CYP2C9*3/*3 required a muchlower dose (1.6 � 0.81 mg/d, n � 5) than those withCYP2C9*1/*3 (3.3 � 0.94 mg/d, n � 18), although mostpatients probably have the VKORC1G/G genotype. Thisresult implies that the patient reported by Mushiroda et al4

may have received an overdose of warfarin or that thispatient’s treatment must have been influenced by otherfactors leading to an increased requirement for warfarin, aspointed out in the article by Aquilante et al.1 Unfortu-

Weight (kg) Dose (mg) Dose/weight (mg/kg)

Women Men Women Men Women Men

65.4 � 10.6 81.6 � 14.4†66.7 � 11.0 80.3 � 16.366.9 � 10.4 73.4 � 13.6 61.9 � 24.5 83.6 � 55.8 0.91 � 0.38 1.38 � 0.8559.5 � 9.4 79.7 � 13.8 16.1 � 8.7 12.5 � 7.7 0.23 � 0.12 0.14 � 0.0668.8 � 15.6 112 (n � 1) 4.1 � 1.6 5.0 � 0.0 0.07 � 0.03 0.045 (n � 1)71.2 � 8.3 85.0 (n � 1) 58.8 � 67.5 26.3 � 19.4 0.35 � 0.04 0.15 (n � 1)63.4 � 9.9 82.2 � 13.9*69.0 � 10.5 83.0 � 15.8 93.3 � 54.8 93.3 � 36.0 1.36 � 1.04 1.20 � 0.5458.9 � 7.0 76.6 � 8.2 4.2 � 1.2 5.2 � 2.5 0.07 � 0.02 0.06 � 0.0256.5 � 0.7 89.2 � 15.8 31.2 � 26.5 35.0 � 13.7 0.56 � 0.48 0.39 � 0.10

Fig 1. Relationship between warfarin maintenance dose andgenotypes. Diamonds, CYP2C9�1/�1; circles, CYP2C9�3/�3.

CLINICAL PHARMACOLOGY & THERAPEUTICS2006;80(5):549-60 Letters to Editor 553