CYP3A5 genotype and midazolam clearance in Australian patients receiving chemotherapy.
OBJECTIVE
Cytochrome P450 (CYP) 3A enzymes are key metabolizing enzymes for many chemotherapeutic agents, and detection of functionally significant CYP3A genetic variants may be useful in predicting interpatient variation of drug clearance. We have examined the significance of CYP3A5*3 single-nucleotide polymorphism to overall CYP3A activity in vivo in a predominantly Caucasian Australian cancer population.


METHODS
Screening for wild-type CYP3A5*1 and CYP3A5*3 single nucleotide polymorphism by use of Taqman MGB probe allelic discrimination was performed in 67 patients with cancer (58 Caucasian patients). CYP3A activity was documented via clearance of either oral or intravenous midazolam in 64 patients.


RESULTS
All patients had at least 1 CYP3A5*3 allele, and 9 (13%) patients were heterozygous for CYP3A5*3 and CYP3A5*1. Within the subset of Caucasian patients, 6 of 58 (10%) were CYP3A5*1/*3 heterozygotes. Mean midazolam clearance was 1.7 times higher in CYP3A5*1/*3 subjects than in CYP3A5*3/*3 subjects (95% confidence interval, 1.15-2.51; P =.01, 2-way ANOVA).


CONCLUSIONS
Overall CYP3A activity is related to CYP3A5 genotype. CYP3A5 genotyping may be helpful in predicting the drug-metabolizing capability of individual cancer patients who are predominantly Caucasian in origin.
Wong
Mark
M
Westmead Institute for Cancer Research, and Department of Translational Oncology, Westmead and Nepean Hospitals, Westmead, New South Wales, Australia.mark_wong@wmi.usyd.edu.au
Balleine
Rosemary L
RL
Collins
Michael
M
Liddle
Christopher
C
Clarke
Christine L
CL
Gurney
Howard
H
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001315:Australia; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D016014:Linear Models; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D008874:Midazolam / Q000493:pharmacokinetics*; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics
D000970:Antineoplastic Agents; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam