Impact of genetic variation in breast cancer resistance protein (BCRP/ABCG2) on sunitinib pharmacokinetics.
To elucidate the impact of genetic variations in breast cancer resistance protein (BCRP/ABCG2) and P-glycoprotein (MDR1/ABCB1) on the pharmacokinetics of sunitinib, we carried out a pharmacogenetic study in a clinical setting and pharmacokinetic analysis using Abcg2(-/-), Abcb1a/1b(-/-) and Abcb1a/1b;Abcg2(-/-) mice. Nineteen renal cell carcinoma patients were enrolled in this study. The plasma concentrations of sunitinib and its active metabolite were determined and the area under the concentration-time curve (AUC) was calculated. Genetic polymorphisms in ABCG2 (421C>A) and ABCB1 (1236C>T, 2677G>T/A and 3435C>T) were examined. The dose-adjusted AUC(0-24) of sunitinib was significantly higher in patients with a heterozygous variant for ABCG2 421C>A than in wild-type patients (p = 0.02), and one homozygous patient showed the highest dose-adjusted AUC(0-24). The ABCB1 polymorphisms were not associated with the dose-adjusted AUC(0-24). The maximum concentration and AUC(0-4) of sunitinib were significantly higher in Abcg2(-/-), Abcb1a/1b(-/-) and Abcb1a/1b;Abcg2(-/-) mice than wild-type mice when sunitinib was given orally but not intraperitoneally. Incidence of thrombocytopenia and hypertension and poor compliance were associated with the systemic exposure to sunitinib and its active metabolite. These results suggest that the loss of protein expression of ABCG2 by genetic polymorphism is associated with an increase in the systemic exposure to sunitinib and sunitinib-induced toxicity.
Department of Pharmacy, Kyoto University Hospital, Kyoto, Japan.
Tomoyuki
T
Mizuno
Masahide
M
Fukudo
Tomohiro
T
Terada
Tomomi
T
Kamba
Eijiro
E
Nakamura
Osamu
O
Ogawa
Ken-Ichi
K
Inui
Toshiya
T
Katsura
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000818:Animals; D019540:Area Under Curve; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005260:Female; D005838:Genotype; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000097:blood / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D011758:Pyrroles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012189:Retrospective Studies; D000077210:Sunitinib; D055815:Young Adult
C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D007211:Indoles; D009363:Neoplasm Proteins; D011758:Pyrroles; D000077210:Sunitinib