Effect of ABCG2 genotypes on the pharmacokinetics of A771726, an active metabolite of prodrug leflunomide, and association of A771726 exposure with serum uric acid level.
OBJECTIVE
It has been reported that leflunomide and its active metabolite, A771726, are substrates of the ABCG2 (BCRP) transporter in vitro. Recent genome-wide association studies have shown that ABCG2 transporter modulates serum uric acid (UA) levels. We explored the role of ABCG2 genotypes in the pharmacokinetics of A771726 and the relationship between serum UA levels and pharmacokinetics of A771726 in healthy participants.


METHODS
Twenty-four healthy individuals were recruited and genotyped for ABCG2. After administration of a single dose of 20 mg leflunomide, plasma concentrations of A771726 were measured. Serum UA levels were measured just before medication, and ABCG2 c.421C>A and c.34G> A polymorphism were genotyped.


RESULTS
ABCG2 c.421C>A but not c.34G>A substantially influenced the pharmacokinetics of A771726. A771726 C(max) was 30% higher, area under the concentration-time curve (AUC) 83% larger, and oral clearance (CL/F) 41% lower in c.421C>A carriers than in noncarriers. Serum UA levels were also higher in carriers than in noncarriers and exhibited a strong and positive correlation with A771726 AUC (Spearman r = 0.6746, P = 0.0003), but a negative correlation was observed with A771726 CL/F (Spearman r = -0.6616, P = 0.0004).


CONCLUSIONS
ABCG2 c.421C>A but not c.34G>A polymorphism appears to be a major determinant of interindividual variability in A771726 disposition. Additionally, serum UA levels exhibited a strong correlation with exposure to A771726.
Department of Clinical Pharmacology and Toxicology, Anam Hospital, Korea University College of Medicine, 126-1 Anam-dong 5-ga, Sungbuk-gu, Seoul 136-705, Korea.
Kyoung-Ah
KA
Kim
Hyun-Jin
HJ
Joo
Ji-Young
JY
Park
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism*; D000814:Aniline Compounds / Q000097:blood / Q000493:pharmacokinetics*; D003437:Crotonates; D005838:Genotype; D006801:Humans; D006885:Hydroxybutyrates / Q000097:blood / Q000493:pharmacokinetics*; D007555:Isoxazoles / Q000493:pharmacokinetics*; D000077339:Leflunomide; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism*; D009570:Nitriles; D020641:Polymorphism, Single Nucleotide; D011355:Prodrugs / Q000493:pharmacokinetics*; D021381:Protein Transport; D014052:Toluidines; D014527:Uric Acid / Q000097:blood*
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000814:Aniline Compounds; D003437:Crotonates; D006885:Hydroxybutyrates; D007555:Isoxazoles; D009363:Neoplasm Proteins; D009570:Nitriles; D011355:Prodrugs; D014052:Toluidines; C527525:teriflunomide; D014527:Uric Acid; D000077339:Leflunomide