scholarly journals Imbalance of Drug Transporter-CYP450s Interplay by Diabetes and Its Clinical Significance

Pharmaceutics ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 348 ◽  
Author(s):  
Yiting Yang ◽  
Xiaodong Liu
Keyword(s):  
Drug Transport ◽  
Drug Disposition ◽  
Organic Anion ◽  
Efflux Transporters ◽  
Cancer Resistance ◽  
Cytochrome P450 Enzymes ◽  
Organic Anion Transporting Polypeptides ◽  
Glycoprotein P ◽  
Anion Transporters ◽  
Associated Proteins

The pharmacokinetics of a drug is dependent upon the coordinate work of influx transporters, enzymes and efflux transporters (i.e., transporter-enzyme interplay). The transporter–enzyme interplay may occur in liver, kidney and intestine. The influx transporters involving drug transport are organic anion transporting polypeptides (OATPs), peptide transporters (PepTs), organic anion transporters (OATs), monocarboxylate transporters (MCTs) and organic cation transporters (OCTs). The efflux transporters are P-glycoprotein (P-gp), multidrug/toxin extrusions (MATEs), multidrug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP). The enzymes related to drug metabolism are mainly cytochrome P450 enzymes (CYP450s) and UDP-glucuronosyltransferases (UGTs). Accumulating evidence has demonstrated that diabetes alters the expression and functions of CYP450s and transporters in a different manner, disordering the transporter–enzyme interplay, in turn affecting the pharmacokinetics of some drugs. We aimed to focus on (1) the imbalance of transporter-CYP450 interplay in the liver, intestine and kidney due to altered expressions of influx transporters (OATPs, OCTs, OATs, PepTs and MCT6), efflux transporters (P-gp, BCRP and MRP2) and CYP450s (CYP3As, CYP1A2, CYP2E1 and CYP2Cs) under diabetic status; (2) the net contributions of these alterations in the expression and functions of transporters and CYP450s to drug disposition, therapeutic efficacy and drug toxicity; (3) application of a physiologically-based pharmacokinetic model in transporter–enzyme interplay.

scholarly journals Prediction of Cyclosporin-Mediated Drug Interaction Using Physiologically Based Pharmacokinetic Model Characterizing Interplay of Drug Transporters and Enzymes

2020 ◽  
Vol 21 (19) ◽  
pp. 7023
Author(s):  
Yiting Yang ◽  
Ping Li ◽  
Zexin Zhang ◽  
Zhongjian Wang ◽  
Li Liu ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Pbpk Model ◽  
Drug Disposition ◽  
Organic Anion ◽  
Whole Body ◽  
Efflux Transporters ◽  
Cytochrome P450 Enzymes ◽  
Control Drug ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

Uptake transporter organic anion transporting polypeptides (OATPs), efflux transporters (P-gp, BCRP and MRP2) and cytochrome P450 enzymes (CYP450s) are widely expressed in the liver, intestine or kidney. They coordinately work to control drug disposition, termed as “interplay of transporters and enzymes”. Cyclosporine A (CsA) is an inhibitor of OATPs, P-gp, MRP2, BCRP and CYP3As. Drug–drug interaction (DDI) of CsA with victim drugs occurs via disordering interplay of transporters and enzymes. We aimed to establish a whole-body physiologically-based pharmacokinetic (PBPK) model which predicts disposition of CsA and nine victim drugs including atorvastatin, cerivastatin, pravastatin, rosuvastatin, fluvastatin, simvastatin, lovastatin, repaglinide and bosentan, as well as drug–drug interactions (DDIs) of CsA with nine victim drugs to investigate the integrated effect of enzymes and transporters in liver, intestinal and kidney on drug disposition. Predictions were compared with observations. Most of the predictions were within 0.5–2.0 folds of observations. Atorvastatin was represented to investigate individual contributions of transporters and CYP3As to atorvastatin disposition and their integrated effect. The contributions to atorvastatin disposition were hepatic OATPs >> hepatic CYP3A > intestinal CYP3As ≈ efflux transporters (P-gp/BCRP/MRP2). The results got the conclusion that the developed PBPK model characterizing the interplay of enzymes and transporters was successfully applied to predict the pharmacokinetics of 10 OATP substrates and DDIs of CsA with 9 victim drugs.

scholarly journals Enantioselective Drug Recognition by Drug Transporters

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3062 ◽  
Author(s):  
Yuichi Uwai
Keyword(s):  
Drug Transporters ◽  
Organic Anion ◽  
Cancer Resistance ◽  
Multidrug Resistance Proteins ◽  
Inhibitory Effects ◽  
Organic Anion Transporting Polypeptides ◽  
Resistance Proteins ◽  
Anion Transporters ◽  
Resistance Protein ◽  
The Relationship

Drug transporters mediate the absorption, tissue distribution, and excretion of drugs. The cDNAs of P-glycoprotein, multidrug resistance proteins (MRPs/ABCC), breast cancer resistance protein (BCRP/ABCG2), peptide transporters (PEPTs/SLC15), proton-coupled folate transporters (PCFT/SLC46A1), organic anion transporting polypeptides (OATPs/SLCO), organic anion transporters (OATs/SLC22), organic cation transporters (OCTs/SLC22), and multidrug and toxin extrusions (MATEs/SLC47) have been isolated, and their functions have been elucidated. Enantioselectivity has been demonstrated in the pharmacokinetics and efficacy of drugs, and is important for elucidating the relationship with recognition of drugs by drug transporters from a chiral aspect. Enantioselectivity in the transport of drugs by drug transporters and the inhibitory effects of drugs on drug transporters has been summarized in this review.

scholarly journals Expression and Function of Organic Anion Transporting Polypeptides in the Human Brain: Physiological and Pharmacological Implications

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 834
Author(s):  
Anima M. Schäfer ◽  
Henriette E. Meyer zu Schwabedissen ◽  
Markus Grube
Keyword(s):  
Organic Anion ◽  
Physiological Role ◽  
Point Of View ◽  
Efflux Transporters ◽  
Organic Anion Transporting Polypeptides ◽  
Current State ◽  
P Glycoprotein ◽  
The Central Nervous System ◽  
And Function ◽  
Uptake Transporters

The central nervous system (CNS) is an important pharmacological target, but it is very effectively protected by the blood–brain barrier (BBB), thereby impairing the efficacy of many potential active compounds as they are unable to cross this barrier. Among others, membranous efflux transporters like P-Glycoprotein are involved in the integrity of this barrier. In addition to these, however, uptake transporters have also been found to selectively uptake certain compounds into the CNS. These transporters are localized in the BBB as well as in neurons or in the choroid plexus. Among them, from a pharmacological point of view, representatives of the organic anion transporting polypeptides (OATPs) are of particular interest, as they mediate the cellular entry of a variety of different pharmaceutical compounds. Thus, OATPs in the BBB potentially offer the possibility of CNS targeting approaches. For these purposes, a profound understanding of the expression and localization of these transporters is crucial. This review therefore summarizes the current state of knowledge of the expression and localization of OATPs in the CNS, gives an overview of their possible physiological role, and outlines their possible pharmacological relevance using selected examples.

scholarly journals Tenofovir and Severe Symptomatic Hypophosphatemia

2019 ◽  
Vol 7 ◽  
pp. 232470961984879 ◽  
Author(s):  
Asim Kichloo ◽  
Savneek Singh Chugh ◽  
Sanjeev Gupta ◽  
Jay Panday ◽  
Ghazaleh Goldar
Keyword(s):  
Renal Damage ◽  
Organic Anion ◽  
Significant Risk ◽  
Anion Transporters ◽  
Immunodeficiency Virus ◽  
Tubular Lumen ◽  
Associated Proteins ◽  
Proximal Tubular ◽  
Renal Tubular ◽  
Initial Results

Tenofovir is a broadly used drug used for the treatment of human immunodeficiency virus (HIV). Although the initial results of the clinical trials supported the renal safety of Tenofovir, clinical use of it has caused a low, albeit a significant, risk of renal damage either in the form of AKI or CKD. The pathophysiology has been linked to the effect of this medication on the proximal tubular cell. Although the exact mechanism is unknown, studies have suggested that Tenofovir accumulates in proximal tubular cells which are rich in mitochondria. It is both filtered in the glomerulus and actively secreted in the tubules for elimination and is excreted unchanged in the urine. Studies have shown an active transportation of 20-30% of this drug into the renal proximal tubule (PCT) cells via the organic anion transporters in the baso-lateral membrane (primarily hOAT1, and OAT3 to a lesser extent) and ultimate excretion of the drug into the tubular lumen via the transporters in the proximal tubular apical membrane MRP4 and MRP2 (multidrug resistance-associated proteins 2 & 4). Subsequently, the mitochondrial injury caused by Tenofovir can lead to the development of Fanconi’s syndrome which causes renal tubular acidosis, phosphaturia, aminoaciduria, glucosuria with normoglycemia, and tubular proteinuria. Here we present a case where Tenofovir treatment resulted in severe hypophosphatemia requiring hospitalization for parentral phosphate repletion.

Statin Drug Interactions in Patients with Comorbidities and on Multiple Medications

2012 ◽  
Vol 08 (02) ◽  
pp. 104 ◽  
Author(s):  
Matthew K Ito ◽  
Keyword(s):  
Drug Interactions ◽  
Drug Transport ◽  
Organic Anion ◽  
The Elderly ◽  
Statin Treatment ◽  
Glycoprotein P ◽  
Beneficial Effects ◽  
Drug Classes ◽  
Wide Range ◽  
Statin Drug

Extensive clinical evidence has demonstrated the efficacy of statin treatment in the prevention of cardiovascular disease (CVD). However, nearly half of patients taking statins discontinue their use, largely as a result of side effects. Many patients receiving statins are elderly, and/or have comorbid conditions, increasing the potential for drug-drug interactions (DDIs). Statin DDIs are largely the result of altered drug metabolism via cytochrome P450s (CYPs), glucuronidation or altered drug transport via organic anion-transporting polypeptides (OATPs) and P-glycoprotein (P-gp). There is a need for discussion and education about DDIs within the clinical consultation. Statins that are not significantly metabolized via the CYP system have a reduced risk of DDIs. To date, pitavastatin has shown a low rate of DDIs compared to other available statins metabolized by CYP3A4 isozymes. Its potential for CYP-mediated DDIs has been studied in combination with a wide range of drug classes known to be CYP inhibitors and has been clinically evaluated in patients populations where multiple medications are used, including the elderly, those high risk of CVD, and those taking protease inhibitors. It may also have beneficial effects on parameters of glucose metabolism, and has shown improved outcomes in patients with chronic kidney disease. Knowledge of statin pharmacokinetics, their dose limitations and contraindications, and their mechanisms of DDI allows improved therapeutic choices, avoiding adverse interactions without compromising patient care.

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