P-Glycoprotein- and cytochrome P-450-mediated herbal drug interactions

The literature on cimetidine drug interactions has been thoroughly reviewed. Several different mechanisms have been proposed for cimetidine-related drug interactions. These mechanisms include: (1) impaired hepatic drug metabolism due to inhibition of hepatic microsomal enzymes, (2) reduced hepatic blood flow, resulting in decreased clearance of drugs that are highly extracted by the liver, (3) increased potential for myelosuppression when administered concurrently with other drugs capable of causing myelosuppression, and (4) altered bioavailability of acid-labile drugs. Cimetidine binds reversibly to the hepatic cytochrome P-450 and P-448 systems, resulting in decreased metabolism of drugs that undergo Phase I reactions (e.g., dealkylation and hydroxylation). In contrast, glucuronidation pathways are unaffected. The rapid onset and reversal of cimetidine's inhibition of hepatic metabolism indicates an effect on hepatic enzyme systems. Cimetidine also has been reported to decrease hepatic blood flow. Drugs that are highly extracted by the liver, such as propranolol, lidocaine, and morphine, may be postulated to have a decreased hepatic clearance. Cimetidine, through its effect on gastric pH, may increase the absorption of acid-labile drugs or may decrease the absorption of drugs. There have been reports of increased potential for myelosuppression when cimetidine is administered concurrently with drugs capable of causing bone marrow suppression. An understanding of the mechanisms involved in cimetidine drug interactions allows the clinician to prevent and predict these interactions.

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A Prediction Method for P-glycoprotein–Mediated Drug–Drug Interactions at the Human Blood–Brain Barrier From Blood Concentration–Time Profiles, Validated With PET Data

Journal of Pharmaceutical Sciences ◽

10.1016/j.xphs.2017.03.024 ◽

2017 ◽

Vol 106 (9) ◽

pp. 2780-2786 ◽

Cited By ~ 1

Author(s):

Akihiro Matsuda ◽

Rudolf Karch ◽

Martin Bauer ◽

Alexander Traxl ◽

Markus Zeitlinger ◽

...

Keyword(s):

Drug Interactions ◽

Blood Brain Barrier ◽

Human Blood ◽

Blood Concentration ◽

Prediction Method ◽

Brain Barrier ◽

Time Profiles ◽

Concentration Time ◽

P Glycoprotein ◽

Blood Brain

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Examination of CYP3A and P-Glycoprotein-Mediated Drug–Drug Interactions Using Animal Models

Methods in Molecular Biology - Multi-Drug Resistance in Cancer ◽

10.1007/978-1-60761-416-6_17 ◽

2009 ◽

pp. 385-403 ◽

Cited By ~ 6

Author(s):

Punit H. Marathe ◽

A. David Rodrigues

Keyword(s):

Animal Models ◽

Drug Interactions ◽

P Glycoprotein

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HMG-CoA reductase inhibitors (Statins) and their Drug Interactions involving CYP enzymes, P-glycoprotein and OATP Transporters - An Overview

Current Drug Metabolism ◽

10.2174/1389200222666210114122729 ◽

2021 ◽

Vol 22 ◽

Author(s):

Rajkapoor Balasubramanian ◽

Naina Mohamed Pakkir Maideen

Keyword(s):

Drug Interactions ◽

Plasma Concentrations ◽

Cochrane Library ◽

Hmg Coa Reductase ◽

Cyp Enzymes ◽

Reductase Inhibitors ◽

P Glycoprotein ◽

Elevated Liver Enzymes ◽

Hmg Coa Reductase Inhibitors ◽

Coa Reductase

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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Herbal Drug Interactions

Complementary and Alternative Medicine and Kidney Health - Advances in Medical Diagnosis, Treatment, and Care ◽

10.4018/978-1-5225-2882-1.ch008 ◽

2017 ◽

pp. 201-231 ◽

Cited By ~ 1

Author(s):

Mymoona Akhter

Keyword(s):

Drug Interaction ◽

Side Effects ◽

Adverse Effects ◽

Drug Interactions ◽

Herbal Medicines ◽

Herbal Drugs ◽

Herbal Drug ◽

Herbal Therapy ◽

Alternative Medicines ◽

Regulatory Bodies

Use of complementary and alternative medicines (CAM) for preventive and therapeutic purposes has increased tremendously in the last two decades internationally. The manufacturers of these products are not required to submit proof of safety or efficacy to the Food and Drug Administration. As a result, the adverse effects and drug interactions associated with them are largely unknown. In this chapter, the author presents interactions of herbal medicines with other medicines (herbal or non-herbal). A large number of herbal drugs, including from single drug to a variety of mixtures have been used to treat kidney disorders. Herb-herb or herb drug interaction has been reported intensively during last decade, therefore it becomes important to keep an eye on the use of combination herbal therapy in order to avoid serious results because of interactions with each other. Due to the growing awareness about the interactions and side effects of herbal drugs/supplements over the past few years, regulatory bodies are working on these issues and pharmacopoeias are being developed for reference.

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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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