Impact of CYP2D6*10 on H1-antihistamine-induced hypersomnia.
OBJECTIVE
This study investigated the relevance of the cytochrome P450 (CYP) 2D6 genotype to the adverse drug reactions (ADRs) of H1-antihistamines and the level of sedation.


METHODS
Japanese participants in a health screening program were asked to describe any past history of ADRs. Any subjects reporting ADRs induced by H1-antihistamines were then individually interviewed and defined as cases. Excessive daytime sleepiness, which had occurred in the cases as an H1-antihistamine-induced ADR, was assessed by the Epworth sleepiness scale (ESS), and an ESS score >or=12 was considered hypersomnia. CYP2D6*4, *5, *14, and *10 were genotyped by a panel of polymerase chain reaction techniques.


RESULTS
Out of 2,074 participants, 100 cases (M:F = 37:63, mean age 51.9 +/- 9.2 years) were eligible for analysis. The most common etiological drug was chlorpheniramine, which is the most frequently used H1-antihistamine in Japan. CYP2D6*10 allele and genotypes were more frequently found in the cases than in the healthy Japanese population in a large study (P < 0.005 and P = 0.039, respectively), but no difference was observed in the null alleles and genotypes. The ESS scores in 75 cases (M:F=25:50) who had experienced excessive daytime sleepiness were 9.5 +/- 5.5 in men and 12.9 +/- 6.1 in women (P < 0.001, cases vs. 34 subjects without symptoms; P = 0.001 men vs. women). The occurrence of hypersomnia increased as the number of CYP2D6 mutant alleles increased (P = 0.045).


CONCLUSIONS
The results suggest that the presence of the CYP2D6*10 allele is a risk factor for development of H1-antihistamine-induced ADRs in Japanese.
Saruwatari
Junji
J
Division of Pharmacology and Therapeutics, Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Oe-honmachi 5-1, Kumamoto 862-0973, Japan.
Matsunaga
Masayuki
M
Ikeda
Kazuyuki
K
Nakao
Masashi
M
Oniki
Kentaro
K
Seo
Takayuki
T
Mihara
Shuichi
S
Marubayashi
Toru
T
Kamataki
Tetsuya
T
Nakagawa
Kazuko
K
D044466:Asian People / Q000235:genetics; D002744:Chlorpheniramine / Q000009:adverse effects; D002974:Clemastine / Q000009:adverse effects; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D006970:Disorders of Excessive Somnolence / Q000139:chemically induced* / Q000175:diagnosis / Q000208:ethnology; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D005787:Gene Frequency; D005820:Genetic Testing / Q000379:methods / Q000706:statistics & numerical data; D005838:Genotype; D006634:Histamine H1 Antagonists / Q000009:adverse effects*; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods; D010640:Phenothiazines / Q000009:adverse effects; D011398:Promethazine / Q000009:adverse effects; D012141:Respiratory Tract Infections / Q000175:diagnosis / Q000188:drug therapy; D012220:Rhinitis / Q000175:diagnosis / Q000188:drug therapy; D012307:Risk Factors; D011795:Surveys and Questionnaires; D014581:Urticaria / Q000175:diagnosis / Q000188:drug therapy; D014987:Xerostomia / Q000139:chemically induced
D006634:Histamine H1 Antagonists; D010640:Phenothiazines; D002744:Chlorpheniramine; D002974:Clemastine; D019389:Cytochrome P-450 CYP2D6; D011398:Promethazine; C006069:mequitazine