Genetic polymorphisms of the Human H+/ dipeptide transporter PEPTZ in Singapore and its effects on cephalexin pharmacokinetics

Abstract

The H+/peptide co-transporter 2 (PEPT2, SLC15A2) is highly expressed in the kidney, predominantly contributing to the renal reabsorption of di- and tri-peptides as well as many peptide-like drugs such as beta-lactam antibiotics and angiotensin-converting enzyme inhibitors. Thus the functional changes of PEPT2 are thought to potentially affect the renal clearance of PEPT2?s drug substrates.

I conducted a series of studies to (1) characterize the population frequencies of PEPT2 polymorphic variants in three Asian ethnic populations residing in Singapore, namely Chinese, Malay and Asian Indian; (2) investigate the associations of ethnicity (Chinese vs Asian Indian), PEPT2 polymorphic variants and pharmacokinetics of cephalexin, a model substrate of PEPT2 in healthy Asian subjects; (3) examine the effects of urinary pH modifiers (ammonium chloride vs sodium bicarbonate) pre-treatment on PEPT2 mediated renal clearance of cephalexin in healthy Asian subjects.

I found that: (1) in total, 10 common single nucleotide polymorphisms (SNPs) were detected in the 3 ethnic populations residing in Singapore, forming 2 PEPT2 haplotypes. There were significant ethnic differences in PEPT2 haplotype distribution: the frequencies of PEPT2*1 and PEPT2*2 allele were 0.307 and 0.693 in Chinese; 0.495 and 0.505 in Malay; 0.729 and 0.271 in Asian Indian, respectively; (2) under fasting conditions: Cmax of cephalexin was significantly lower in Chinese (29.80 ? 4.09 ng/ml) than in Asian Indian (33.29 ? 4.97 ng/ml, p=0.045) healthy subjects. This difference could be explained by the lower average body weight in Chinese subjects. There was no other significant difference in cephalexin pharmacokinetics between either ethnic or PEPT2 genotypic groups; (3) The mean renal clearance of cephalexin was significantly higher under ammonium chloride than under sodium bicarbonate pre-treatment (P < 0.01). This difference significant was observed for PEPT2*2/*2 (P = 0.017) but not for PEPT2*1/*1 (P = 0.128) genotypic group. No differences were observed for the other pharmacokinetic parameters.

These findings suggest that (1) there are significant differences in PEPT2 polymorphic variant distributions among the three ethnic populations residing in Singapore, namely Chinese, Malay and Asian Indians; (2) cephalexin pharmacokinetics is similar in Chinese and Asian Indian; (3) urinary pH modifiers (ammonium chloride and sodium bicarbonate) can alter the renal clearance of PEPT2?s substrates and this effect was more obvious for the PEPT2*2/*2 carriers.