Carriers of the UGT1A4 142T>G gene variant are predisposed to reduced olanzapine exposure--an impact similar to male gender or smoking in schizophrenic patients.
OBJECTIVE
The impact of the UGT1A4, CYP1A2, and MDR1 genetic variants on olanzapine plasma levels, in relation to those of other individual factors, such as gender, smoking status, body weight, and age, was investigated in patients with schizophrenia.


METHODS
A total of 121 patients were recruited from psychosis-specialized outpatient departments in Stockholm County. Olanzapine plasma concentrations were determined by high-performance liquid chromatography. Genotyping was carried out by PCR-restriction fragment length polymorphism or minisequencing, and haplotypes were analyzed using specialized computer software on population genetics. Multiple regression analysis was performed to investigate the combined effect of patient characteristics and genotypes/haplotypes on daily dose-corrected plasma concentrations of olanzapine.


RESULTS
In addition to , the results indicate that inter-patient differences in olanzapine exposure were explained by the known factor of time of sampling from last dose intake and by the following individual factors in order of relative impact: (1) male gender, (2) carrier of the UGT1A4 142T>G single nucleotide polymorphism (SNP), and (3) smoking. Each of these three factors predicted a decrease in daily dose-corrected plasma concentrations of 35, 25, and 21%, respectively. In contrast, age, body weight, and MDR1 or CYP1A2 haplotype did not have a significant impact.


CONCLUSIONS
At 12 h after dose intake, the regression model predicted a 5.1-fold higher olanzapine plasma level in a non-smoking female patient who did not carry the UGT1A4 142T>G SNP compared to a smoking man treated with the same dose but heterozygous for UGT1A4 142T>G SNP. Whether these combined genetic and environmental factors influence the risk of therapeutic failure remains to be established.
Ghotbi
Roza
R
Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska University Hospital Huddinge-Karolinska Institutet, 141 86, Stockholm, Sweden.
Mannheimer
Buster
B
Aklillu
Eleni
E
Suda
Akira
A
Bertilsson
Leif
L
Eliasson
Erik
E
Osby
Urban
U
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D014150:Antipsychotic Agents / Q000097:blood* / Q000627:therapeutic use; D001569:Benzodiazepines / Q000097:blood* / Q000627:therapeutic use; D001835:Body Weight; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D012727:Sex Characteristics; D012907:Smoking / Q000009:adverse effects
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014150:Antipsychotic Agents; C019787:bilirubin glucuronoside glucuronosyltransferase; D001569:Benzodiazepines; D019388:Cytochrome P-450 CYP1A2; D014453:Glucuronosyltransferase; D000077152:Olanzapine