Comparative Hepatic and Intestinal Efflux Transport of Statins

Deng, Feng; Tuomi, Suvi-Kukka; Neuvonen, Mikko; Hirvensalo, Päivi; Kulju, Sami; Wenzel, Christoph; Oswald, Stefan; Filppula, Anne M.; Niemi, Mikko

doi:10.1124/dmd.121.000430

Cited by 35 publications

(41 citation statements)

References 53 publications

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“…To determine the regulation of P‐gp by NHERF‐1, CTCs and BeWo cells were treated with rosuvastatin (one of the statin drugs and a substrate to P‐gp) at different points (Figure 3A and 3B). P‐gp transports rosuvastatin in hepatic and intestinal transport systems 39,40 . As anticipated, both CTCs and BeWo cells showed expression patterns similar to NHERF‐1 and P‐gp at different time points after substrate stimulation (Figure 3C and 3D).…”

Section: Resultssupporting

confidence: 70%

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Functional role and regulation of permeability‐glycoprotein (P‐gp) in the fetal membrane during drug transportation

Kammala

Benson

Ganguly

et al. 2021

American J Rep Immunol

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Objective: Na + /H + exchange regulatory factor-1 (NHERF-1) is a class I PDZ (PSD95/Discs-large/ZO-1) binding protein involved in cell-surface expression and stabilization of transporter proteins, including permeability-glycoprotein (P-gp) in various cell types. P-gp, expressed in placental trophoblasts, is an efflux transporter protein that influences the pharmacokinetics of various drugs used during pregnancy. Previously we have reported that NHERF-1 regulates fetal membrane inflammation. However, the role of NHERF-1 in regulating P-gp in the fetal membrane during drug transportation remains unclear. This study determined the interplay between NHERF-1 and P-gp in human fetal membrane cells.Methods: Fetal membranes from normal, term cesareans were screened for P-gp by immunohistochemistry (IHC). Chorionic trophoblast (CTC), with the highest expression of P-gp among fetal membrane cells, was further used to test interactive properties between NHERF-1 and P-gp. BeWo (placental trophoblast cell line) cells were used as a control. Immunoprecipitation (IP) of CTC lysates using the P-gp antibody followed by western blot determined co-precipitation of NHERF-1. Silencing NHERF-1 using small interfering RNA further tested the relevance of NHERF-1 in P-gp expression and function in CTC and BeWo cells. NHERF-1 regulation of P-gp's efflux function (drug resistance) was further tested using the ENZO TM efflux dye kit.Results: Immunohistochemistry localized, and western blot confirmed P-gp in human fetal membranes, primarily in the CTC with limited expression in the amnion epithelial layer. P-gp expression in the membranes was similar to that seen in the placenta.IP data showed P-gp co-precipitating with NHERF1. Silencing of NHERF-1 resulted in significant drug resistance suggesting P-gp function mediated through NHERF1 in CTCs. Conclusion:Proinflammatory mediator NHERF-1 regulates P-gp and control drug transportation across the fetal membranes. Our data suggest a novel functional role for fetal membranes during pregnancy. Besides the placenta, fetal membranes may also

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Section: Resultssupporting

confidence: 70%

“…P-gp transports rosuvastatin in hepatic and intestinal transport systems. 39,40 As anticipated, both CTCs and BeWo cells showed expression patterns similar to NHERF-1 and P-gp at different time points after substrate stimulation (Figure 3C and 3D).…”

Section: Expression Of P-gp and Nherf1 In Ctc And Bewo Cells After St...supporting

confidence: 71%

Functional role and regulation of permeability‐glycoprotein (P‐gp) in the fetal membrane during drug transportation

Kammala

Benson

Ganguly

et al. 2021

American J Rep Immunol

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“…[2][3][4][5][6] Some studies have suggested that simvastatin acid is also a substrate of the P-glycoprotein, 13,14 an efflux transporter encoded by the ABCB1 gene, although the evidence is contradictory. 15 Evidence as to the effect of genetic variation in ABCB1 on simvastatin pharmacokinetics is unclear. [16][17][18] As the risk for muscle-related adverse effects increases along with simvastatin exposure, 1,4,5 understanding the genetic variants affecting simvastatin pharmacokinetics is important.…”

Section: Articlementioning

confidence: 99%

“…The SLCO1B1 c.521T>C (p.Val174Ala, rs4149056) missense variant raises simvastatin acid exposure and increases the risk for adverse effects 2–6 . Some studies have suggested that simvastatin acid is also a substrate of the P‐glycoprotein, 13,14 an efflux transporter encoded by the ABCB1 gene, although the evidence is contradictory 15 . Evidence as to the effect of genetic variation in ABCB1 on simvastatin pharmacokinetics is unclear 16–18 …”

mentioning

confidence: 99%

Genomewide Association Study of Simvastatin Pharmacokinetics

Mykkänen

Taskinen

Neuvonen

et al. 2022

Clin Pharma and Therapeutics

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We investigated genetic determinants of single‐dose simvastatin pharmacokinetics in a prospective study of 170 subjects and a retrospective cohort of 59 healthy volunteers. In a microarray‐based genomewide association study with the prospective data, the SLCO1B1 c.521T>C (p.Val174Ala, rs4149056) single nucleotide variation showed the strongest, genomewide significant association with the area under the plasma simvastatin acid concentration‐time curve (AUC; P = 6.0 × 10−10). Meta‐analysis with the retrospective cohort strengthened the association (P = 1.6 × 10−17). In a stepwise linear regression candidate gene analysis among all 229 participants, SLCO1B1 c.521T>C (P = 1.9 × 10−13) and CYP3A4 c.664T>C (p.Ser222Pro, rs55785340, CYP3A4*2, P = 0.023) were associated with increased simvastatin acid AUC. Moreover, the SLCO1B1 c.463C>A (p.Pro155Thr, rs11045819, P = 7.2 × 10−6) and c.1929A>C (p.Leu643Phe, rs34671512, P = 5.3 × 10−4) variants associated with decreased simvastatin acid AUC. Based on these results and the literature, we classified the volunteers into genotype‐predicted OATP1B1 and CYP3A4 phenotype groups. Compared with the normal OATP1B1 function group, simvastatin acid AUC was 273% larger in the poor (90% confidence interval (CI), 137%, 488%; P = 3.1 × 10−6), 40% larger in the decreased (90% CI, 8%, 83%; P = 0.036), and 67% smaller in the highly increased function group (90% CI, 46%, 80%; P = 2.4 × 10−4). Intermediate CYP3A4 metabolizers (i.e., heterozygous carriers of either CYP3A4*2 or CYP3A4*22 (rs35599367)), had 87% (90% CI, 39%, 152%, P = 6.4 × 10−4) larger simvastatin acid AUC than normal metabolizers. These data suggest that in addition to no function SLCO1B1 variants, increased function SLCO1B1 variants and reduced function CYP3A4 variants may affect the pharmacokinetics, efficacy, and safety of simvastatin. Care is warranted if simvastatin is prescribed to patients carrying decreased function SLCO1B1 or CYP3A4 alleles.

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“…Assuming that rosuvastatin CL s,efflux was mediated by passive diffusion only, the predicted CL s,efflux was 19% of the reported PET imaging value (Table 2), which suggests that sinusoidal transporter(s), likely MRP4 (but not MRP3), may be involved in the efflux of rosuvastatin. 13,24,25 Unfortunately, we could not include MRP4-mediated sinusoidal efflux in the REF approach because its abundance was not quantifiable in human liver tissue. 4 In contrast, as expected and discussed below, CL s,efflux was drastically overpredicted by the SCH approach (Table 2).…”

Section: Discussionmentioning

confidence: 99%