scholarly journals In Vitro Evaluation of the Drug Interaction Potential of Doravirine

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Kelly Bleasby ◽  
Kerry L. Fillgrove ◽  
Robert Houle ◽  
Bing Lu ◽  
Jairam Palamanda ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Reversible Inhibitor ◽  
Drug Metabolizing Enzymes ◽  
Cancer Resistance ◽  
Metabolizing Enzymes ◽  
Anion Transporter ◽  
Major Drug

ABSTRACT Doravirine is a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus type 1 infection. In vitro studies were conducted to assess the potential for drug interactions with doravirine via major drug-metabolizing enzymes and transporters. Kinetic studies confirmed that cytochrome P450 3A (CYP3A) plays a major role in the metabolism of doravirine, with ∼20-fold-higher catalytic efficiency for CYP3A4 versus CYP3A5. Doravirine was not a substrate of breast cancer resistance protein (BCRP) and likely not a substrate of organic anion transporting polypeptide 1B1 (OATP1B1) or OATP1B3. Doravirine was not a reversible inhibitor of major CYP enzymes (CYP1A2, -2B6, -2C8, -2C9, -2C19, -2D6, and -3A4) or of UGT1A1, nor was it a time-dependent inhibitor of CYP3A4. No induction of CYP1A2 or -2B6 was observed in cultured human hepatocytes; small increases in CYP3A4 mRNA (≤20%) were reported at doravirine concentrations of ≥10 μM but with no corresponding increase in enzyme activity. In vitro transport studies indicated a low potential for interactions with substrates of BCRP, P-glycoprotein, OATP1B1 and OATP1B3, the bile salt extrusion pump (BSEP), organic anion transporter 1 (OAT1) and OAT3, organic cation transporter 2 (OCT2), and multidrug and toxin extrusion 1 (MATE1) and MATE2K proteins. In summary, these in vitro findings indicate that CYP3A4 and CYP3A5 mediate the metabolism of doravirine, although with different catalytic efficiencies. Clinical trials reported elsewhere confirm that doravirine is subject to drug-drug interactions (DDIs) via CYP3A inhibitors and inducers, but they support the notion that DDIs (either direction) are unlikely via other major drug-metabolizing enzymes and transporters.

A Decade’s Review of miRNA: a Center of Transcriptional Regulation of Drug-Metabolizing Enzymes and Transporters Under Hypoxia

2021 ◽  
Vol 22 ◽  
Author(s):  
Yabin Duan ◽  
Junbo Zhu ◽  
Jianxin Yang ◽  
Wenqi Gu ◽  
Xue Bai ◽  
...  
Keyword(s):  
Organic Anion ◽  
Hypoxia Inducible Factor ◽  
Organic Cation Transporter ◽  
Organic Anion Transporter ◽  
Peptide Transporter ◽  
Drug Metabolizing Enzymes ◽  
Cancer Resistance ◽  
Metabolizing Enzymes ◽  
Anion Transporter

Background: Hypoxia has a negative effect on the cardiovascular system, nervous system, and metabolism, which contributes to potential changes in drug absorption, distribution, metabolism, and excretion (ADME). However, hypoxia can also alter the expression of microRNA (miRNA), thereby regulating drug-metabolizing enzymes, transporters, and ADME genes, such as hypoxia-inducible factor, inflammatory cytokine, nuclear receptor, etc. Therefore, it is crucial to study the role of miRNA in the regulation of drug-metabolizing enzymes and transporters under hypoxia. Methods: A systematic review of published studies was carried out to investigate the role of miRNA in the regulation of drug-metabolizing enzymes and transporters under hypoxia. Data and information on expression changes in miRNA, drug-metabolizing enzymes, and transporters under hypoxia were analyzed and summarized Results: Hypoxia can up- or down-regulate the expression of miRNA. The effect of hypoxia on Cytochrome P450 (CYP450) is still a subject of debate. The widespread belief is that hypoxia decreased the activity and expression of CYP1A1, CYP1A2, CYP2E1, and CYP3A1 and increased those of CYP3A6 and CYP2D1 in rats. Hypoxia increased the expression of a multidrug resistance-associated protein, breast cancer resistance protein, peptide transporter, organic cation transporter, and organic anion transporter. miRNA negatively regulated the expression of drug-metabolizing enzymes and transporters. Conclusion: The findings of this review indicated that miRNA plays a key role in the expression changes of drug-metabolizing enzymes and transporters under hypoxia.

scholarly journals Islatravir Is Not Expected to Be a Victim or Perpetrator of Drug-Drug Interactions via Major Drug-Metabolizing Enzymes or Transporters

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1566
Author(s):  
Kelly Bleasby ◽  
Robert Houle ◽  
Michael Hafey ◽  
Meihong Lin ◽  
Jingjing Guo ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Organic Anion ◽  
Organic Cation Transporter ◽  
Organic Anion Transporter ◽  
Uridine Diphosphate ◽  
Cancer Resistance ◽  
Treatment And Prevention ◽  
Anion Transporter

Islatravir (MK-8591) is a nucleoside reverse transcriptase translocation inhibitor in development for the treatment and prevention of HIV-1. The potential for islatravir to interact with commonly co-prescribed medications was studied in vitro. Elimination of islatravir is expected to be balanced between adenosine deaminase–mediated metabolism and renal excretion. Islatravir did not inhibit uridine diphosphate glucuronosyltransferase 1A1 or cytochrome p450 (CYP) enzymes CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4, nor did it induce CYP1A2, 2B6, or 3A4. Islatravir did not inhibit hepatic transporters organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, bile salt export pump (BSEP), multidrug resistance-associated protein (MRP) 2, MRP3, or MRP4. Islatravir was neither a substrate nor a significant inhibitor of renal transporters organic anion transporter (OAT) 1, OAT3, OCT2, multidrug and toxin extrusion protein (MATE) 1, or MATE2K. Islatravir did not significantly inhibit P-glycoprotein and breast cancer resistance protein (BCRP); however, it was a substrate of BCRP, which is not expected to be of clinical significance. These findings suggest islatravir is unlikely to be the victim or perpetrator of drug-drug interactions with commonly co-prescribed medications, including statins, diuretics, anti-diabetic drugs, proton pump inhibitors, anticoagulants, benzodiazepines, and selective serotonin reuptake inhibitors.

scholarly journals In Vitro Inhibitory Effects of APINACA on Human Major Cytochrome P450, UDP-Glucuronosyltransferase Enzymes, and Drug Transporters

Molecules ◽  
2019 ◽  
Vol 24 (16) ◽  
pp. 3000 ◽  
Author(s):  
Sunjoo Kim ◽  
Won-Gu Choi ◽  
Mihwa Kwon ◽  
Sowon Lee ◽  
Yong-Yeon Cho ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Organic Anion ◽  
Liver Microsomes ◽  
Organic Cation Transporter ◽  
Organic Anion Transporter ◽  
Drug Abusers ◽  
Cancer Resistance ◽  
Inhibitory Effects ◽  
Anion Transporter

APINACA (known as AKB48, N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide), an indazole carboxamide synthetic cannabinoid, has been used worldwide as a new psychoactive substance. Drug abusers take various drugs concomitantly, and therefore, it is necessary to characterize the potential of APINACA-induced drug–drug interactions due to the modulation of drug-metabolizing enzymes and transporters. In this study, the inhibitory effects of APINACA on eight major human cytochrome P450s (CYPs) and six uridine 5′-diphospho-glucuronosyltransferases (UGTs) in human liver microsomes, as well as on the transport activities of six solute carrier transporters and two efflux transporters in transporter-overexpressed cells, were investigated. APINACA exhibited time-dependent inhibition of CYP3A4-mediated midazolam 1′-hydroxylation (Ki, 4.5 µM; kinact, 0.04686 min−1) and noncompetitive inhibition of UGT1A9-mediated mycophenolic acid glucuronidation (Ki, 5.9 µM). APINACA did not significantly inhibit the CYPs 1A2, 2A6, 2B6, 2C8/9/19, or 2D6 or the UGTs 1A1, 1A3, 1A4, 1A6, or 2B7 at concentrations up to 100 µM. APINACA did not significantly inhibit the transport activities of organic anion transporter (OAT)1, OAT3, organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic cation transporter (OCT)1, OCT2, P-glycoprotein, or breast cancer resistance protein at concentrations up to 250 μM. These data suggest that APINACA can cause drug interactions in the clinic via the inhibition of CYP3A4 or UGT1A9 activities.

scholarly journals Salvia miltiorrhizaRoots against Cardiovascular Disease: Consideration of Herb-Drug Interactions

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Feng Chen ◽  
Li Li ◽  
Dan-Dan Tian
Keyword(s):  
Drug Interactions ◽  
Phenolic Acids ◽  
Salvia Miltiorrhiza ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Published Data ◽  
Inhibitory Effects ◽  
Anion Transporter

Salvia miltiorrhizaroot (Danshen) is widely used in Asia for its cardiovascular benefits and contains both hydrophilic phenolic acids and lipophilic tanshinones, which are believed to be responsible for its therapeutic efficacy. This review summarized the effects of these bioactive components fromS. miltiorrhizaroots on pharmacokinetics of comedicated drugs with mechanic insights regarding alterations of protein binding, enzyme activity, and transporter activity based on the published data stemming from bothin vitroandin vivohuman studies.In vitrostudies indicated that cytochrome P450 (CYP450), carboxylesterase enzyme, catechol-O-methyltransferase, organic anion transporter 1 (OAT1) and OAT3, and P-glycoprotein were the major targets involved inS. miltiorrhiza-drug interactions. Lipophilic tanshinones had much more potent inhibitory effects towards CYPs activities compared to hydrophilic phenolic acids, evidenced by much lowerKivalues of the former. ClinicalS. miltiorrhiza-drug interaction studies were mainly conducted using CYP1A2 and CYP3A4 probe substrates. In addition, the effects of coexisting components on the pharmacokinetic behaviors of those noted bioactive compounds were also included herein.

scholarly journals Comprehensive Substrate Characterization of 22 Antituberculosis Drugs for Multiple Solute Carrier (SLC) Uptake TransportersIn Vitro

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
M. M. Parvez ◽  
Nazia Kaisar ◽  
Ho Jung Shin ◽  
Yoon Jae Lee ◽  
Jae-Gook Shin
Keyword(s):  
Drug Interactions ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Antituberculosis Drugs ◽  
Hek 293 ◽  
Slc Transporters ◽  
Anion Transporter ◽  
Solute Carrier

ABSTRACTThe substrate potentials of antituberculosis drugs on solute carrier (SLC) transporters are not well characterized to date, despite a well-established understanding of their drug dispositions and pharmacokinetics. In this study, we investigated comprehensively the substrate potentials of the 22 currently available antituberculosis drugs for SLC family transporter-mediated uptake, usingXenopus laevisoocytes and stably transfected HEK-293 cellsin vitro. The result suggested that ethambutol, isoniazid, amoxicillin, and prothionamide act as novel substrates for the SLC transporters. In addition, in the presence of representative transporter inhibitors, the uptake of the antituberculosis drugs was markedly decreased compared with the uptake in the absence of inhibitor, suggesting involvement of the corresponding transporters. A cellular uptake study was performed, and theKmvalues of ethambutol were found to be 526.1 ± 15.6, 212.0 ± 20.1, 336.8 ± 20.1, and 455.0 ± 28 μM for organic cation transporter 1 (OCT1), OCT2, OCTN1, and OCTN2, respectively. Similarly, theKmof prothionamide was 805.8 ± 23.4 μM for OCT1, while theKmvalues of isoniazid and amoxicillin for organic anion transporter 3 (OAT3) were 233.7 ± 14.1 and 161.4 ± 10.6 μM, respectively. The estimatedin vivodrug-drug interaction indexes fromin vitrotransporter inhibition kinetics for verapamil, probenecid, and ibuprofen against ethambutol, prothionamide, isoniazid, and amoxicillin were found to show potential for clinical drug interactions. In conclusion, this is the first study that demonstrated 22 antituberculosis drug interactions with transporters. This study will be helpful for mechanistic understanding of the disposition, drug-drug interactions, and pharmacokinetics of these antituberculosis drugs.

scholarly journals Evaluation of Chinese-Herbal-Medicine-Induced Herb-Drug Interactions: Focusing on Organic Anion Transporter 1

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Chang-Ching Lin ◽  
Hsien-Yuan Fan ◽  
Chien-Wen Kuo ◽  
Li-Heng Pao
Keyword(s):  
Drug Interactions ◽  
Mrna Expression ◽  
Prescription Drugs ◽  
Drug Transport ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Chinese Herbal ◽  
Anion Transporter

The consumption of Chinese herbal medicines (CHMs) is increasing exponentially. Many patients utilize CHMs concomitantly with prescription drugs in great frequency. Herb-drug interaction has hence become an important focus of study. Transporter-mediated herb-drug interactions have the potential to seriously influence drug efficacy and toxicity. Since organic anion transporter 1 (OAT1) is crucial in renal active secretion and drug-drug interactions, the possibility of modulation of OAT1-mediated drug transport should be seriously concerned. Sixty-three clinically used CHMs were evaluated in the study. An hOAT1-overexpressing cell line was used for thein vitroCHMs screening, and the effective candidates were administered to Wistar rats to access renal hemodynamics. The regulation of OAT1 mRNA expression was also examined for further evidence of CHMs affecting OAT1-mediated transport. Among all the 63 CHMs, formulae Gui Zhi Fu Ling Wan (GZ) and Chia Wei Hsiao Yao San (CW) exhibited significant inhibitions on hOAT1-mediated [3H]-PAH uptakein vitroand PAH clearance and net secretionin vivo. Moreover, GZ showed concentration-dependent manners bothin vitroandin vivo, and the decrease of rOAT1 mRNA expression indicated that GZ not only inhibited function of OAT1 but also suppressed expression of OAT1.

scholarly journals Application of a PBPK Model of Rivaroxaban to Prospective Simulations of Drug-Drug-Disease Interactions with Protein Kinase Inhibitors in CA-VTE

2021 ◽  
Author(s):  
Eleanor Jing Yi Cheong ◽  
Daniel Zhi Wei Ng ◽  
Sheng Yuan Chin ◽  
Ziteng Wang ◽  
Eric Chun Yong Chan
Keyword(s):  
Protein Kinase ◽  
Kinase Inhibitors ◽  
Pbpk Model ◽  
Organic Anion ◽  
Protein Kinase Inhibitors ◽  
Organic Anion Transporter ◽  
Pbpk Modelling ◽  
Anion Transporter

Background and Purpose Rivaroxaban is emerging as a viable anticoagulant for the pharmacological management of cancer associated venous thromboembolism (CA-VTE). Being eliminated via CYP3A4/2J2-mediated metabolism and organic anion transporter 3 (OAT3)/P-glycoprotein-mediated renal secretion, rivaroxaban is susceptible to drug-drug interactions (DDIs) with protein kinase inhibitors (PKIs), erlotinib and nilotinib. Physiologically based pharmacokinetic (PBPK) modelling was applied to interrogate the DDIs for dose adjustment of rivaroxaban in CA-VTE. Experimental Approach The inhibitory potencies of erlotinib and nilotinib on CYP3A4/2J2-mediated metabolism of rivaroxaban were characterized. Using prototypical OAT3 inhibitor ketoconazole, in vitro OAT3 inhibition assays were optimized to ascertain the in vivo relevance of derived inhibitory constants (K). DDIs between rivaroxaban and erlotinib or nilotinib were investigated using iteratively verified PBPK model. Key Results Mechanism-based inactivation (MBI) of CYP3A4-mediated rivaroxaban metabolism by both PKIs and MBI of CYP2J2 by erlotinib were established. The importance of substrate specificity and nonspecific binding to derive OAT3-inhibitory K values of ketoconazole and nilotinib for the accurate prediction of DDIs was illustrated. When simulated rivaroxaban exposure variations with concomitant erlotinib and nilotinib therapy were evaluated using published dose-exposure equivalence metrics and bleeding risk analyses, dose reductions from 20 mg to 15 mg and 10 mg in normal and mild renal dysfunction, respectively, were warranted. Conclusion and Implications We established the PBPK-DDI platform to prospectively interrogate and manage clinically relevant interactions between rivaroxaban and PKIs in patients with underlying renal impairment. Rational dose adjustments were proposed, attesting to the capacity of PBPK modelling in facilitating precision medicine.

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