Effect of multidrug resistance gene-1 (ABCB1) polymorphisms on the single-dose pharmacokinetics of cloxacillin in healthy adult Chinese men.
BACKGROUND
Plasma concentrations of cloxacillin have been found to vary as much as 20-fold among individuals receiving the same oral dose. There is evidence that cloxacillin may be a substrate for P-glycoprotein, suggesting that polymorphisms in the ABCB1 gene may be a contributing factor to the observed variability in plasma cloxacillin concentrations.


OBJECTIVE
This study investigated the effect of ABCB1 polymorphisms on the pharmacokinetic profile of cloxacillin in healthy subjects.


METHODS
A single oral dose of cloxacillin 500 mg was administered to healthy Chinese male subjects under fasting conditions. Serial blood and urine samples were collected for up to 6 hours after administration. A high-performance liquid chromatography method was used to determine plasma cloxacillin pharmacokinetics and urinary excretion. A polymerase chain reaction technique was used for genotyping of 3 single nucleotide polymorphisms (SNPs) of the ABCB1 gene: exon 12 C1236T, exon 21 G2677T/A, and exon 26 C3435T. Cloxacillin pharmacokinetic parameters and urinary excretion were then compared according to genotype and haplotype groups.


RESULTS
The study included 18 healthy Chinese male subjects who ranged in age from 21 to 26 years, had a mean weight ranging from 55.6 to 70.6 kg, and had normal renal function at baseline (mean [SD] serum creatinine, 93.4 [11.0] micromol/L). Plasma concentrations of cloxacillin were generally lower in the group carrying the 1236CC genotype (n = 3) compared with those carrying the 1236CT genotype (n = 9) or the 1236TT genotype (n = 6). Compared with the other groups, carriers of the 1236CC genotype had a significantly lower mean Cmax (-53%; P = 0.013) and AUC(0-infinity) (-40%; P = 0.044), and a significantly higher mean apparent oral clearance (35%; P = 0.013). They also had significantly lower urinary excretion of cloxacillin over 6 hours (-52%; P = 0.027). There were no significant differences in cloxacillin t(1/2) or renal clearance between the 3 C1236T genotypes, nor was the G2677T or C3435T SNP associated with any significant changes in the cloxacillin pharmacokinetic profile. Among subjects with 1 of the 3 major haplotype pairs, those carrying the CGC/CGC pair had a significantly lower C(max) (P = 0.017), AUC (P = 0.032), and urinary excretion of cloxacillin (P = 0.026) compared with those carrying the CGC/TGC and TTT/TTT pairs.


CONCLUSIONS
In this small population of healthy Chinese men, the C1236T variant of ABCB1 appeared to be an important contributor to interindi-vidual differences in plasma cloxacillin exposure, most likely through an effect on oral absorption rather than on disposition. Studies of multiple doses in larger sample sizes are needed to confirm these findings.
Yin
Ophelia Q P
OQ
School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong. Ophelia.yin@novartis.com
Tomlinson
Brian
B
Chow
Moses S S
MS
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000097:blood / Q000235:genetics* / Q000652:urine; D000284:Administration, Oral; D000328:Adult; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D044466:Asian People / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid; D003023:Cloxacillin / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D019450:Genes, MDR / Q000235:genetics*; D006801:Humans; D008297:Male; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012016:Reference Values; D055815:Young Adult
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000900:Anti-Bacterial Agents; D003023:Cloxacillin