Evaluation of P-glycoprotein–Mediated Renal Drug Interactions in an MDR1-MDCK Model

Background: Hydroxymethyl glutaryl-CoA (HMG-CoA) reductase inhibitors (Statins) are used to treat dyslipidemia. Generally, the statins are the substrates of CYP enzymes, P-glycoprotein (P-gp), and organic anion transporting polypeptides transporters (OATP1B1). Objective: This review article focuses on the clinical significance of statins, and their interactions in real practice. Method: The databases like Medline/PubMed Central/PubMed, Google Scholar, Science Direct, Cochrane Library, Directory of open access journals (DOAJ), and reference lists were searched to identify relevant articles. Results: Most of the drug interactions of statins result in elevated plasma concentrations and toxicity of statins due to the inhibition of CYP3A4, P-gp and/or OATP1B1 transporters. The toxicity of statins includes myopathy, rhabdomyolysis, elevated liver enzymes, acute kidney injury, and diabetes. The statins like Simvastatin, Lovastatin, and Atorvastatin are substrates of CYP3A4 enzyme and P-glycoprotein and their concomitant use with the drugs inhibiting or inducing them would result in changes in plasma concentrations and toxicity/efficacy. However, the statins like Pravastatin, Rosuvastatin and Pitavastatin are not substrates of CYP enzymes and hence the concomitant use of CYP inhibitors or inducers do not affect them. Almost all the statins are the substrates of OATP1B1 transporter, and the co-prescription of inhibitors of OATP1B1 elevates the plasma concentrations and muscle toxicity of statins. Conclusion: Understanding the interacting potential of each statin will enable the prescribers, pharmacists, and other health care professionals to use statins effectively without compromising patient safety.

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Citrus auraptene induces drug efflux transporter P-glycoprotein expression in human intestinal cells

Food & Function ◽

10.1039/d0fo00315h ◽

2020 ◽

Vol 11 (6) ◽

pp. 5017-5023 ◽

Cited By ~ 2

Author(s):

Tomohiro Nabekura ◽

Tatsuya Kawasaki ◽

Yu Kato ◽

Kazuyoshi Kawai ◽

Serena Fiorito ◽

...

Keyword(s):

Protein Expression ◽

Drug Interactions ◽

Intestinal Cells ◽

Drug Efflux ◽

Efflux Transporter ◽

Glycoprotein Gene ◽

P Glycoprotein ◽

Human Intestinal Cells

Citrus phytochemical auraptene activates the drug efflux transporter P-glycoprotein gene (MDR1) promoter in human intestinal LS174T cells. Auraptene increases protein expression of P-glycoprotein. Auraptene can cause food–drug interactions.

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In Vitro Interaction of AB-FUBINACA with Human Cytochrome P450, UDP-Glucuronosyltransferase Enzymes and Drug Transporters

Molecules ◽

10.3390/molecules25194589 ◽

2020 ◽

Vol 25 (19) ◽

pp. 4589 ◽

Cited By ~ 1

Author(s):

Sunjoo Kim ◽

Dong Kyun Kim ◽

Yongho Shin ◽

Ji-Hyeon Jeon ◽

Im-Sook Song ◽

...

Keyword(s):

Drug Interactions ◽

Organic Anion ◽

Liver Microsomes ◽

Drug Abusers ◽

Cancer Resistance ◽

Mixed Inhibition ◽

P Glycoprotein ◽

Human Cytochrome

AB-FUBINACA, a synthetic indazole carboxamide cannabinoid, has been used worldwide as a new psychoactive substance. Because drug abusers take various drugs concomitantly, it is necessary to explore potential AB-FUBINACA-induced drug–drug interactions caused by modulation of drug-metabolizing enzymes and transporters. In this study, the inhibitory effects of AB-FUBINACA on eight major human cytochrome P450s (CYPs) and six uridine 5′-diphospho-glucuronosyltransferases (UGTs) of human liver microsomes, and on eight clinically important transport activities including organic cation transporters (OCT)1 and OCT2, organic anion transporters (OAT)1 and OAT3, organic anion transporting polypeptide transporters (OATP)1B1 and OATP1B3, P-glycoprotein, and breast cancer resistance protein (BCRP) in transporter-overexpressing cells were investigated. AB-FUBINACA inhibited CYP2B6-mediated bupropion hydroxylation via mixed inhibition with Ki value of 15.0 µM and competitively inhibited CYP2C8-catalyzed amodiaquine N-de-ethylation, CYP2C9-catalyzed diclofenac 4′-hydroxylation, CYP2C19-catalyzed [S]-mephenytoin 4′-hydroxylation, and CYP2D6-catalyzed bufuralol 1′-hydroxylation with Ki values of 19.9, 13.1, 6.3, and 20.8 µM, respectively. AB-FUBINACA inhibited OCT2-mediated MPP+ uptake via mixed inhibition (Ki, 54.2 µM) and competitively inhibited OATP1B1-mediated estrone-3-sulfate uptake (Ki, 94.4 µM). However, AB-FUBINACA did not significantly inhibit CYP1A2, CYP2A6, CYP3A4, UGT1A1, UGT1A3, UGT1A4, UGT1A6, or UGT2B7 enzyme activities at concentrations up to 100 µM. AB-FUBINACA did not significantly inhibit the transport activities of OCT1, OAT1/3, OATP1B3, P-glycoprotein, or BCRP at concentrations up to 250 μM. As the pharmacokinetics of AB-FUBINACA in humans and animals remain unknown, it is necessary to clinically evaluate potential in vivo pharmacokinetic drug–drug interactions induced by AB-FUBINACA-mediated inhibition of CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, OCT2, and OATP1B1 activities.

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