ABCB1 c.2677G&gt;T/c.3435C&gt;T diplotype increases the early-phase oral absorption of losartan

Shin, Hyo-Bin; Jung, Eui Hyun; Kang, Pureum; Lim, Chang Woo; Oh, Kyung-Yul; Cho, Chang‐Keun; Lee, Yun Jeong; Choi, Chang‐Ik; Jang, Choon‐Gon; Lee, Seok‐Yong; Bae, Jung‐Woo

doi:10.1007/s12272-020-01294-3

Cited by 22 publications

(5 citation statements)

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“…In this study, having the reference genotype (T/T) in any of the three ABCB1 variants analyzed (rs1045642 T>C, rs1128503 T>C and rs2032582 T>G/A) slowed valsartan absorption. Our findings hence suggest that valsartan is a P-gp substrate, like other drugs of the ARB family, such as losartan or candesartan [23,24]. In this research, the association between t max and the ABCB1 rs1045642 T/T genotype was reinforced by its association with a higher postural dizziness incidence.…”

Section: Discussionmentioning

confidence: 50%

“…Valsartan and hydrochlorothiazide pharmacokinetics were altered by ABCB1 and SLC22A1 genetic variation, respectively. ABCB1 codes for the P-glycoprotein (P-gp) transporter, located in enterocytes, renal cells, hepatocytes and blood-brain barrier cells [23]. In this study, having the reference genotype (T/T) in any of the three ABCB1 variants analyzed (rs1045642 T>C, rs1128503 T>C and rs2032582 T>G/A) slowed valsartan absorption.…”

Section: Discussionmentioning

confidence: 74%

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Impact of Sex and Genetic Variation in Relevant Pharmacogenes on the Pharmacokinetics and Safety of Valsartan, Olmesartan and Hydrochlorothiazide

Soria-Chacartegui,

Zubiaur,

Ochoa

et al. 2023

IJMS

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Drug combination therapy is the most common pharmacological strategy for hypertension management. No pharmacogenetic biomarkers for guiding hypertension pharmacotherapy are available to date. The study population were 64 volunteers from seven bioequivalence trials investigating formulations with valsartan, olmesartan and/or hydrochlorothiazide. Every volunteer was genotyped for 10 genetic variants in different transporters’ genes. Additionally, valsartan-treated volunteers were genotyped for 29 genetic variants in genes encoding for different metabolizing enzymes. Variability in pharmacokinetic parameters such as maximum concentration (Cmax) and time to reach it (tmax), the incidence of adverse drug reactions (ADRs) and blood pressure measurements were analyzed as a function of pharmacogenetic and demographic parameters. Individuals with the ABCB1 rs1045642 T/T genotype were associated with a higher valsartan tmax compared to those with T/G and G/G genotypes (p < 0.001, β = 0.821, R2 = 0.459) and with a tendency toward a higher postural dizziness incidence (11.8% vs. 0%, p = 0.070). A higher hydrochlorothiazide dose/weight (DW)-corrected area under the curve (AUC∞/DW) was observed in SLC22A1 rs34059508 G/A volunteers compared to G/G volunteers (p = 0.050, β = 1047.35, R2 = 0.051), and a tendency toward a higher postural dizziness incidence (50% vs. 1.6%, p = 0.063). Sex impacted valsartan and hydrochlorothiazide pharmacokinetics, showing a lower exposure in women, whereas no significant differences were found for olmesartan pharmacokinetics.

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Section: Discussionmentioning

confidence: 50%

Section: Discussionmentioning

confidence: 74%

Impact of Sex and Genetic Variation in Relevant Pharmacogenes on the Pharmacokinetics and Safety of Valsartan, Olmesartan and Hydrochlorothiazide

Soria-Chacartegui,

Zubiaur,

Ochoa

et al. 2023

IJMS

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“…Quite a recent report by Shin et al concluded that the plasma levels of losartan and EXP3174 were not in uenced by the C3435T and G2677T/A polymorphisms, but that these polymorphisms might substantially increase the early-phase absorption of losartan [11]. Although it was revealed in our study that C3435T, G2677T/A, and C1236T polymorphisms did not bring about a change in the plasma losartan and EXP3174 levels, we could not evaluate the effects of these polymorphisms on the earlyphase absorption of the drug because our patients had long been under losartan treatment.…”

Section: Discussionmentioning

confidence: 99%

Investigation of MDR1 Gene Polymorphism and Losartan Plasma Concentration in Patients Undergoing Hypertensive Episodes While under Losartan Treatment

Cimen,

Tug,

Nesetoglu

et al. 2023

Preprint

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Purpose: Losartan, a drug in the angiotensin receptor blocker (ARB) family, is the substrate of the Multi Drug Resistance-1 (MDR1) drug-efflux protein encoded by the ABCB1 gene. This study seeks to investigate the MDR1 gene polymorphism and losartan concentration in order to identify drug resistance in patients presenting to the emergency department (ED) with a hypertensive episode while having losartan treatment. Methods: The ethics approval of our study was granted by Gazi University Clinical Research Ethics Committee (dateof registration 23.10.2017, number: 496) and Ministry of Health Turkey Medicines and Medical Devices Agency (date of registration 14.02.2018, code number: 17-AKD-189). The patient cohort was comprised of 50 individuals presenting with a hypertensive episode while under losartan treatment. The control cohort included 50 patients whose blood pressure was regulated while receiving losartan treatment and who were admitted to the ED for reasons other than hypertensive episode. Allele-specific analysis was carried out PCR (Polymerase Chain Reaction) device. Plasma losartan and EXP3174 levels of the patients were measured using tandem mass spectrometry. Results: The frequencies of GG, GT, GA, TA and TT genotypes did not differ significantly between the cohorts in G2677T/A single nucleotide polymorphism (SNP) (p>0.05), whereas those of C3435T TT and C1236T CT genotypes yielded a significant difference between the patient and control cohorts (p<0.05). Conclusion: We provided clinical evidence that hypertensive episodes occurred more frequently in C3435T TT and less frequently in C1236T CT. However, no significant correlation was established between plasma losartan, EXP3174 concentration and G2677T/A, C3435T, and C1236T genotypes. American Clinical Trials Registration Number: NCT05349825

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“…It also inhibited P-gp, BCRP, and OATP1B1 activity levels, which transfer drugs into or out of the cells. Previous studies have demonstrated that P-gp, BCRP, and OATP1B1 play a crucial role in the absorption, distribution, and excretion of LOS in vivo ( Pei et al, 2018 ; Ripperger et al, 2018 ; Shin et al, 2020 ). However, certain other drug transporters may participate in the metabolism of LOS in rat.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Potential Herb-Drug Interactions Between Shengmai Injection and Losartan Potassium in Rat and In Vitro

et al. 2022

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Aim: The present study aimed to explore the potential herb-drug interactions (HDI) between Shengmai injection (SMI) and losartan potassium (LOS) based on the expression profiles of cytochromes P450 (CYP450) and drug transporters in rat and in vitro.Methods: Different concentrations of SMI were used to explore the influence of SMI on the antihypertensive efficacy of LOS in the hypertension rat model established by N (omega)-nitro-L-arginine methyl ester (L-NAME) for 4 weeks. Subsequently, the serum concentration levels of LOS and losartan carboxylic acid (EXP3174) were determined by Liquid Chromatography Mass Spectrometry (LC-MS) and pharmacokinetic analysis. Human liver microsomes, human multidrug resistance protein 1 (MDR1/P-gp), and breast cancer resistance protein (BCRP) vesicles, human embryonic kidney 293 cell line with stable expression of the organic anion transporting polypeptide 1B1 (HEK293-OATP1B1 cells) and mock-transfected HEK293 (HEK293-MOCK) cells were used to verify the effects of SMI on CYP450 enzymes and drug transporters in vitro.Results: Low, medium, and high concentrations of SMI increased the antihypertensive efficacy of LOS to varying degrees. The high dose SMI increased the half-life (t1/2), the maximum plasma concentration (Cmax), the area under the plasma concentration-time curve (AUC) from time zero to the time of the last measurable plasma concentration (AUC0-t), AUC from time zero to infinity (AUC0-∞), and mean residence time (MRT) values of LOS and decreased its apparent volume of distribution (Vd) and clearance (CL) values. The AUC0-t, AUC0-∞, and MRT of LOS were increased, whereas the CL was decreased by the medium concentration of SMI. In addition, the high, medium, and low doses of SMI increased the relative bioavailability (Frel) of LOS. SMI exhibited no significant effects on the pharmacokinetics of EXP3174. In vitro, SMI exhibited different suppressive effects on the enzyme activity levels of CYP1A2 (6.12%), CYP2B6 (2.72%), CYP2C9 (14.31%), CYP2C19 (12.96%), CYP2D6 (12.26%), CYP3A4 (3.72%), CYP2C8 (10.00–30.00%), MDR1 (0.75%), OATP1B1(2.03%), and BCRP (0.15%).Conclusion: In conclusion, SMI improved the antihypertensive efficacy of LOS in the L-NAME-induced hypertension rat model by increasing the concentration of LOS, while leaving the concentration of EXP3174 intact. SMI affected the pharmacokinetic properties of LOS by decreasing the elimination of LOS. These effects might partly be attributed to the inhibition of the activities of CYP3A4, CYP2C9, and of the drug transporters (P-gp, BCRP, and OATP1B1) by SMI, which need further scrutiny.

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ABCB1 c.2677G>T/c.3435C>T diplotype increases the early-phase oral absorption of losartan

Cited by 22 publications

References 50 publications

Impact of Sex and Genetic Variation in Relevant Pharmacogenes on the Pharmacokinetics and Safety of Valsartan, Olmesartan and Hydrochlorothiazide

Impact of Sex and Genetic Variation in Relevant Pharmacogenes on the Pharmacokinetics and Safety of Valsartan, Olmesartan and Hydrochlorothiazide

Investigation of MDR1 Gene Polymorphism and Losartan Plasma Concentration in Patients Undergoing Hypertensive Episodes While under Losartan Treatment

Evaluation of Potential Herb-Drug Interactions Between Shengmai Injection and Losartan Potassium in Rat and In Vitro

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