The ABCG2 C421A polymorphism does not affect oral nitrofurantoin pharmacokinetics in healthy Chinese male subjects

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• An increasing number of drugs on the market or under development have been identified as substrates of the ATP-binding cassette drug efflux transporter breast cancer resistance protein (BCRP; ABCG2), which can affect the pharmacokinetics of drugs by reducing absorption and/or increasing biliary elimination.
• ABCG2 C421A, a single nucleotide polymorphism associated with decreased protein expression/transport activity in vitro and higher anti-cancer drug concentrations in carriers of the C421A polymorphism, may contribute to the intersubject pharmacokinetic variability of BCRP substrates.
• Predicting the potential influence of BCRP on drug disposition or drug interactions is challenging because of the lack of a well-characterized, BCRP-selective clinical probe substrate.
• Nitrofurantoin is potentially a suitable clinical BCRP probe substrate based on preclinical and clinical information available (e.g. in vitro transport studies, Bcrp knockout mouse studies, inhibition studies in rats, and milk secretion studies in rats and humans).

WHAT THIS STUDY ADDS

• The ABCG2 C421A SNP had no effect on oral nitrofurantoin plasma and urine pharmacokinetic parameters in healthy male Chinese subjects.
• Nitrofurantoin does not appear to be a useful clinical BCRP probe.

AIMS

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-∞) (95% confidence interval) values were 2.21 (2.00, 2.45), 2.42 (2.11, 2.78) and 2.32 (1.99, 2.70) µg 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.