The ABCG2 C421A polymorphism does not affect oral nitrofurantoin pharmacokinetics in healthy Chinese male subjects.
OBJECTIVE
A number of drugs are substrates or inhibitors of the efflux transporter breast cancer resistance protein (BCRP; ABCG2), which can limit systemic exposure by reducing absorption and/or increasing biliary elimination. The identification of a BCRP-selective clinical probe drug would provide a useful tool to understand the effect of genetic polymorphisms and transporter-based drug interactions on drug pharmacokinetics. The aim of this study was to assess the utility of nitrofurantoin as a clinical probe substrate for BCRP activity by evaluating the impact of genetic variation on nitrofurantoin pharmacokinetics.


METHODS
Nitrofurantoin pharmacokinetics were studied in an open-label, single-oral dose (100 mg) study in 36 male Chinese subjects who were pre-screened for ABCG2 421 CC, CA and AA genotypes (n = 12 each). Plasma and urine concentrations of nitrofurantoin were determined by LC/MS/MS and LC/UV respectively. anova was used to compare pharmacokinetic parameters among genotypes.


RESULTS
There were no significant differences in nitrofurantoin pharmacokinetics among the genotypic cohorts. The geometric mean nitrofurantoin plasma AUC((0-infinity)) (95% confidence interval) values were 2.21 (2.00, 2.45), 2.42 (2.11, 2.78) and 2.32 (1.99, 2.70) microg h ml(-1) and half-life values were 0.79 (0.59, 1.0), 0.76 (0.64, 0.89) and 0.72 (0.62, 0.84) h for ABCG2 421 genotypes CC, CA and AA, respectively. The percentage of dose excreted unchanged in the urine was 43, 44 and 39%, respectively.


CONCLUSIONS
The ABCG2 C421A polymorphism had no effect on nitrofurantoin plasma and urine pharmacokinetic parameters in healthy Chinese subjects. These results indicate that nitrofurantoin is not a suitable clinical probe substrate for assessing BCRP activity.
Adkison
Kimberly K
KK
Clinical Pharmacokinetics Modelling and Simulation, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. kim.k.adkison@gsk.com
Vaidya
Soniya S
SS
Lee
Daniel Y
DY
Koo
Seok Hwee
SH
Li
Linghui
L
Mehta
Amar A
AA
Gross
Annette S
AS
Polli
Joseph W
JW
Lou
Yu
Y
Lee
Edmund J D
EJ
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000284:Administration, Oral; D000328:Adult; D000892:Anti-Infective Agents, Urinary / Q000008:administration & dosage / Q000493:pharmacokinetics*; D044466:Asian People / Q000235:genetics*; D001692:Biological Transport / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D009582:Nitrofurantoin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic / Q000187:drug effects*; D016896:Treatment Outcome
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000892:Anti-Infective Agents, Urinary; D009363:Neoplasm Proteins; D009582:Nitrofurantoin