title: Variants in the SLCO1B3 gene: interethnic distribution and association with paclitaxel pharmacokinetics.
abstract: To explore retrospectively the relationships between paclitaxel pharmacokinetics and three known, non-synonymous single-nucleotide polymorphisms (SNPs) in SLCO1B3, the gene encoding organic anion transporting polypeptide (OATP)1B3. Accumulation of [(3)H]paclitaxel was studied in Xenopus laevis oocytes injected with cRNA of Oatp1b2, OATP1A2, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, and NTCP. The 334T>G (Ser112Ala), 699G>A (Met233Ile), and 1564G>T (Gly522Cys) loci of SLCO1B3 were screened in 475 individuals from five ethnic groups and 90 European Caucasian cancer patients treated with paclitaxel. Only OATP1B3 was capable of transporting paclitaxel to a significant extent (P=0.003). The 334T>G and 699G>A SNPs were less common in the African-American and Ghanaian populations (P<0.000001). Paclitaxel pharmacokinetics were not associated with the studied SNPs or haplotypes (P>0.3). The studied SNPs in SLCO1B3 appear to play a limited role in the disposition of paclitaxel, although their clinical significance in other ethnic populations remains to be investigated.
authors.affiliation: Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: N F
authors.initials: NF
authors.lastname: Smith
authors.forename: S
authors.initials: S
authors.lastname: Marsh
authors.forename: T J
authors.initials: TJ
authors.lastname: Scott-Horton
authors.forename: A
authors.initials: A
authors.lastname: Hamada
authors.forename: S
authors.initials: S
authors.lastname: Mielke
authors.forename: K
authors.initials: K
authors.lastname: Mross
authors.forename: W D
authors.initials: WD
authors.lastname: Figg
authors.forename: J
authors.initials: J
authors.lastname: Verweij
authors.forename: H L
authors.initials: HL
authors.lastname: McLeod
authors.forename: A
authors.initials: A
authors.lastname: Sparreboom
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006801:Humans; D066298:In Vitro Techniques; D009865:Oocytes; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics*; D017239:Paclitaxel / Q000493:pharmacokinetics*; D020641:Polymorphism, Single Nucleotide; D044469:Racial Groups; D012189:Retrospective Studies; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D014982:Xenopus laevis
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D029362:Organic Anion Transporters, Sodium-Independent; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D017239:Paclitaxel