title: Effect of common CYP3A4 and CYP3A5 variants on the pharmacokinetics of the cytochrome P450 3A phenotyping probe midazolam in cancer patients.
abstract: OBJECTIVE
  To evaluate the effect of naturally occurring variants in genes encoding the cytochrome P450 (CYP) isoforms CYP3A4 and CYP3A5 in patients with cancer receiving midazolam as a phenotyping probe.
  
  
  METHODS
  Five variants in CYP3A4 and CYP3A5 were evaluated in 58 patients (21 women and 37 men) receiving a short i.v. bolus of midazolam (dose, 0.0145 or 0.025 mg/kg). Midazolam concentrations in plasma were determined using liquid chromatography-mass spectrometry, and pharmacokinetic variables were calculated using noncompartmental analysis. Genomic DNA was characterized for the variants by PCR-RFLP, and all genotypes were confirmed by direct nucleotide sequencing.
  
  
  RESULTS
  The mean clearance of midazolam was 24.4 +/- 9.12 L/h, and phenotypic CYP3A activity varied about 4-fold in this population (range, 10.8-44.3 L/h). There were six carriers of the CYP3A4*1B allele (allele frequency, 0.061). No variant alleles for CYP3A4*17, CYP3A4*18A, or CYP3A5*6 were identified. Forty-eight of the 58 patients were homozygous variant for CYP3A5*3C, eight were heterozygous, and two were homozygous wild type (allele frequency, 0.897). No associations were noted between any of the studied genotypes and the phenotypic measures (P > or = 0.16). Likewise, a common variant in exon 26 in the gene encoding P-glycoprotein [i.e., ABCB1 (MDR1) 3435C>T] that was previously reported to be linked to CYP3A4 mRNA levels was unrelated to any of the studied phenotypic measures (P > or = 0.49).
  
  
  CONCLUSIONS
  The studied genetic variants in CYP3A4 and CYP3A5 are unlikely to have an important functional significance to phenotypic CYP3A activity in patients with cancer.
authors.affiliation: Science Applications International Corporation-Frederick, Maryland, USA.
authors.forename: Erin R
authors.initials: ER
authors.lastname: Lepper
authors.forename: Sharyn D
authors.initials: SD
authors.lastname: Baker
authors.forename: Matt
authors.initials: M
authors.lastname: Permenter
authors.forename: Nicole
authors.initials: N
authors.lastname: Ries
authors.forename: Ron H N
authors.initials: RH
authors.lastname: van Schaik
authors.forename: Paul W
authors.initials: PW
authors.lastname: Schenk
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Price
authors.forename: Danielle
authors.initials: D
authors.lastname: Ahn
authors.forename: Nicola F
authors.initials: NF
authors.lastname: Smith
authors.forename: George
authors.initials: G
authors.lastname: Cusatis
authors.forename: Roxann G
authors.initials: RG
authors.lastname: Ingersoll
authors.forename: Susan E
authors.initials: SE
authors.lastname: Bates
authors.forename: Ron H J
authors.initials: RH
authors.lastname: Mathijssen
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.forename: Alex
authors.initials: A
authors.lastname: Sparreboom
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000328:Adult; D000368:Aged; D000483:Alleles; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: C412459:ABCB10 protein, human; D018528:ATP-Binding Cassette Transporters; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam