title: Pharmacogenetics of tipifarnib (R115777) transport and metabolism in cancer patients.
abstract: The purpose of this study was to perform exploratory relationships between the pharmacokinetics of the farnesyl transferase inhibitor, tipifarnib (R115777, Zarnestra) and allelic variants of genes coding for ATP binding-cassette transporters and drug-metabolizing enzymes. Twenty-eight patients with advanced solid tumors were treated with tipifarnib administered orally at a dose of 200 or 300 mg. Blood samples were collected for pharmacokinetics and genotyping of 10 variants in genes encoding P-glycoprotein (ABCB1), cytochrome P450 isozymes CYP3A4 and CYP3A5, and UDP glucuronosyltransferase isozyme UGT1A1. The homozygous T -allele of ABCB1*8 (1236C > T ) was associated with a trend for a higher area under the curve of tipifarnib as compared to patients with only one or no variant alleles [mean (+/-SD), 5,303 +/- 1,620 ng.h/mL vs. 3,619 +/- 1,275 ng.h/mL; P = 0.047). No statistically significant differences were observed with any other genetic variant ( P > 0.15). Overall, this study indicates that ABCB1 genotype might be correlated with tipifarnib pharmacokinetics, although considerable overlap in exposure measures between genotype groups was observed.
authors.affiliation: Clinical Pharmacology Research Core, National Cancer Institute, Bethesda, MD, USA. SparrebA@mail.nih.gov
authors.forename: Alex
authors.initials: A
authors.lastname: Sparreboom
authors.forename: Sharon
authors.initials: S
authors.lastname: Marsh
authors.forename: Ron H J
authors.initials: RH
authors.lastname: Mathijssen
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
authors.forename: Howard L
authors.initials: HL
authors.lastname: McLeod
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001692:Biological Transport; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D015363:Quinolones / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D020080:Tandem Repeat Sequences; D000099148:UGT1A1 Enzyme
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D015363:Quinolones; D000099148:UGT1A1 Enzyme; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; C510163:CYP3A4 protein, human; C402769:tipifarnib