title: Impact of CYP2C8*3 on paclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in 93 patients with ovarian cancer.
abstract: The primary purpose of this study was to evaluate the effect of CYP2C8*3 and three genetic ABCB1 variants on the elimination of paclitaxel. We studied 93 Caucasian women with ovarian cancer treated with paclitaxel and carboplatin. Using sparse sampling and nonlinear mixed effects modeling, the individual clearance of unbound paclitaxel was estimated from total plasma paclitaxel and Cremophor EL. The geometric mean of clearance was 385 l h⁻¹ (range 176-726 l h⁻¹). Carriers of CYP2C8*3 had 11% lower clearance than non-carriers, P=0.03. This has not been shown before in similar studies; the explanation is probably the advantage of using both unbound paclitaxel clearance and a population of patients of same gender. No significant association was found for the ABCB1 variants C1236T, G2677T/A and C3435T. Secondarily, other candidate single-nucleotide polymorphisms were explored with possible associations found for CYP2C8*4 (P=0.04) and ABCC1 g.7356253C>G (P=0.04).
authors.affiliation: Department of Clinical Pharmacology, Institute of Public Health, University of Southern Denmark, Odense, Denmark. tbergmann@health.sdu.dk
authors.forename: T K
authors.initials: TK
authors.lastname: Bergmann
authors.forename: C
authors.initials: C
authors.lastname: Brasch-Andersen
authors.forename: H
authors.initials: H
authors.lastname: Gréen
authors.forename: M
authors.initials: M
authors.lastname: Mirza
authors.forename: R S
authors.initials: RS
authors.lastname: Pedersen
authors.forename: F
authors.initials: F
authors.lastname: Nielsen
authors.forename: K
authors.initials: K
authors.lastname: Skougaard
authors.forename: J
authors.initials: J
authors.lastname: Wihl
authors.forename: N
authors.initials: N
authors.lastname: Keldsen
authors.forename: P
authors.initials: P
authors.lastname: Damkier
authors.forename: L E
authors.initials: LE
authors.lastname: Friberg
authors.forename: C
authors.initials: C
authors.lastname: Peterson
authors.forename: W
authors.initials: W
authors.lastname: Vach
authors.forename: M O
authors.initials: MO
authors.lastname: Karlsson
authors.forename: K
authors.initials: K
authors.lastname: Brosen
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D016190:Carboplatin / Q000493:pharmacokinetics / Q000627:therapeutic use; D065727:Cytochrome P-450 CYP2C8; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000493:pharmacokinetics* / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011153:Population / Q000235:genetics
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D016190:Carboplatin; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D017239:Paclitaxel