Tamsulosin Alters the Pharmacokinetics of Metformin Via Inhibition of Renal Multidrug and Toxin Extrusion Protein 1 and Organic Cation Transporter 2 in Rats

2021 ◽  
Author(s):  
Abdulaziz Ahmed A.Saad ◽  
Fan zhang ◽  
Moath Refata ◽  
Eyad Abdulwhab H.Mohammed ◽  
Mingkang Zhang ◽  
...  
Keyword(s):  
Organic Cation ◽  
Organic Cation Transporter ◽  
Organic Cation Transporter 2 ◽  
Toxin Extrusion

scholarly journals Renal secretion of hydrochlorothiazide involves organic anion transporter 1/3, organic cation transporter 2, and multidrug and toxin extrusion protein 2-K

2019 ◽  
Vol 317 (4) ◽  
pp. F805-F814
Author(s):  
Jia Yin ◽  
David J. Wagner ◽  
Bhagwat Prasad ◽  
Nina Isoherranen ◽  
Kenneth E. Thummel ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Organic Cation ◽  
Organic Anion ◽  
Organic Cation Transporter ◽  
Tubular Secretion ◽  
Organic Anion Transporter ◽  
Anion Transporters ◽  
Anion Transporter ◽  
Organic Cation Transporter 2 ◽  
Toxin Extrusion

Hydrochlorothiazide (HCTZ) is the most widely used thiazide diuretic for the treatment of hypertension either alone or in combination with other antihypertensives. HCTZ is mainly cleared by the kidney via tubular secretion, but the underlying molecular mechanisms are unclear. Using cells stably expressing major renal organic anion and cation transporters [human organic anion transporter 1 (hOAT1), human organic anion transporter 3 (hOAT3), human organic cation transporter 2 (hOCT2), human multidrug and toxin extrusion 1 (hMATE1), and human multidrug and toxin extrusion 2-K (hMATE2-K)], we found that HCTZ interacted with both organic cation and anion transporters. Uptake experiments further showed that HCTZ is transported by hOAT1, hOAT3, hOCT2, and hMATE2-K but not by hMATE1. Detailed kinetic analysis coupled with quantification of membrane transporter proteins by targeted proteomics revealed that HCTZ is an excellent substrate for hOAT1 and hOAT3. The apparent affinities ( Km) for hOAT1 and hOAT3 were 112 ± 8 and 134 ± 13 μM, respectively, and the calculated turnover numbers ( kcat) were 2.48 and 0.79 s−1, respectively. On the other hand, hOCT2 and hMATE2-K showed much lower affinity for HCTZ. The calculated transport efficiency ( kcat/ Km) at the single transporter level followed the rank order of hOAT1> hOAT3 > hOCT2 and hMATE2-K, suggesting a major role of organic anion transporters in tubular secretion of HCTZ. In vitro inhibition experiments further suggested that HCTZ is not a clinically relevant inhibitor for hOAT1 or hOAT3. However, strong in vivo inhibitors of hOAT1/3 may alter renal secretion of HCTZ. Together, our study elucidated the molecular mechanisms underlying renal handling of HCTZ and revealed potential pathways involved in the disposition and drug-drug interactions for this important antihypertensive drug in the kidney.

scholarly journals Atenolol Renal Secretion Is Mediated by Human Organic Cation Transporter 2 and Multidrug and Toxin Extrusion Proteins

2015 ◽  
Vol 43 (12) ◽  
pp. 1872-1881 ◽  
Author(s):  
Jia Yin ◽  
Haichuan Duan ◽  
Yoshiyuki Shirasaka ◽  
Bhagwat Prasad ◽  
Joanne Wang
Keyword(s):  
Organic Cation ◽  
Organic Cation Transporter ◽  
Renal Secretion ◽  
Organic Cation Transporter 2 ◽  
Toxin Extrusion
Sign in / Sign up

Export Citation Format

Share Document