ABCB1 c.2677G>T/c.3435C>T diplotype increases the early-phase oral absorption of losartan
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Online ISSN 1976-3786 Print ISSN 0253-6269
RESEARCH ARTICLE
ABCB1 c.2677G>T/c.3435C>T diplotype increases the early‑phase oral absorption of losartan Hyo‑Bin Shin1 · Eui Hyun Jung1 · Pureum Kang1 · Chang Woo Lim1 · Kyung‑Yul Oh1 · Chang‑Keun Cho1 · Yun Jeong Lee2 · Chang‑Ik Choi3 · Choon‑Gon Jang1 · Seok‑Yong Lee1 · Jung‑Woo Bae4
Received: 16 November 2020 / Accepted: 19 November 2020 / Published online: 29 November 2020 © The Pharmaceutical Society of Korea 2020
Abstract Losartan has been shown to be a substrate of the drug-efflux transporter MDR1, encoded by the ABCB1 gene. ABCB1 c.2677G>T and c.3435C>T variants are known to be associated with reduced expression and function of P-glycoprotein (P-gp). We investigated the effects of ABCB1 diplotype on the pharmacokinetics of losartan. Thirty-eight healthy Korean volunteers with different ABCB1 diplotypes [c.2677G> T and c.3435C>T; carriers of GG/CC (n = 13), GT/CT (n = 12) and TT/TT (n = 13) diplotype] were recruited and administered a single 50 mg oral dose of losartan potassium. Losartan and its active metabolite E-3174 samples in plasma and urine were collected up to 10 and 8 h after drug administration, respectively, and the concentrations of both samples were determined by HPLC method. Significant differences were observed in Cmax of losartan and losartan plus E-3174 (Lo + E) among the three diplotype groups (both P T/A, rs2032582) and exon 26 (c.3435C>T, rs1045642) are of particular interest because they are associated with differences in the expression and function. Hoffmeyer et al. (2000) suggested that the ABCB1 c.3435C>T was associated with a lower level of intestinal MDR1 expression. In addition, it was reported that the ABCB1 c.2677G>T/A is also linked to a lower function of P-gp (Kim et al. 2001; Siegmund et al. 2002). It has been suggested that c.3435C>T could act by reducing mRNA stability or by affecting the timing of folding and membrane insertion of the protein, resulting in a change in substrate specificity (Wang et al. 2005; Kimchi-Sarfaty et al. 2007; Fung et al. 2014). Therefore, these common SNPs of ABCB1 gene may exert influence on the pharmacokinetics of P-gp substrate. It was reported that losartan is transported by P-gp and other intestinal transports that do not include ABCC1 (MRP1) and ABCC2 (MRP2) in vitro (Soldner et al. 2000). Göktaş et al. (2016) reported that hypertensive patients with MDR1 3435T allele may present a better response to losartan treatment. However, Yasar et al. (2008) reported that in an in vivo study, urinary concentrations of losartan or E-3174 were not significantly affected by ABCB1 c.3435C>T genetic polymorphism. There have not been detailed studies on the relationship between the genetic polymorphism of ABCB1 and the pharmacokinetics of losartan. Thus, the effects of ABCB1 diplotype, c.2677G>T
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and c.3435C>T, on the pharmacokinetics of losartan and its active metabolite E-3174 were evaluated in this study.
Materials and methods Subjects Thirty-eight healthy Korean subjects were rec
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