Atypical Enzyme Kinetics: Their Effect on In Vitro-In Vivo Pharmacokinetic Predictions and Drug Interactions

Introduction. Since drug interactions may result in serious adverse effects or failure of therapy, it is of huge importance that health professionals base their decisions about drug prescription, dispensing and administration on reliable research evidence, taking into account the hierarchy of data sources for evaluation. Clinical Significance of Potential Interactions - Information Sources. The sources of data regarding drug interactions are numerous, beginning with various drug reference books. However, they are far from uniformity in the way of choosing and presenting putative clinically relevant interactions. Clinical Significance of Potential Interactions - Interpretation of Information. The difficulties in interpretation of drug interactions are illustrated through the analysis of a published example involving assessment made by two different groups of health professionals. Systematic Evaluation of Drug-Drug Interaction. The potential for interactions is mainly investigated before marketing a drug. Generally, the in vitro, followed by in vivo studies are to be performed. The major metabolic pathways involved in the metabolism of a new molecular entity, as well as the potential of induction of human enzymes involved in drug metabolism are to be examined. In the field of interaction research it is possible to make use of the population pharmacokinetic studies as well as of the pharmacodynamic assessment, and also the postregistration monitoring of the reported adverse reactions and other literature data. Conclusion. In vitro and in vivo drug metabolism and transport studies should be conducted to elucidate the mechanisms and potential for drug-drug interactions. The assessment of their clinical significance should be based on well-defined and validated exposure-response data.

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Characterization of the In Vitro Inhibitory Potential of the Oligonucleotide Imetelstat on Human Cytochrome P450 Enzymes with Predictions of In Vivo Drug-Drug Interactions

Drug Metabolism and Disposition ◽

10.1124/dmd.118.084103 ◽

2018 ◽

Vol 47 (1) ◽

pp. 9-14 ◽

Cited By ~ 3

Author(s):

Faraz Kazmi ◽

Carlo Sensenhauser ◽

Tony Greway

Keyword(s):

Cytochrome P450 ◽

Drug Interactions ◽

Cytochrome P450 Enzymes ◽

Human Cytochrome ◽

Inhibitory Potential

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Prediction of Pharmacokinetic Drug-Drug Interactions Using Human Hepatocyte Suspension in Plasma and Cytochrome P450 Phenotypic Data. II. In Vitro-in Vivo Correlation with Ketoconazole

Drug Metabolism and Disposition ◽

10.1124/dmd.107.018796 ◽

2008 ◽

Vol 36 (7) ◽

pp. 1255-1260 ◽

Cited By ~ 30

Author(s):

Chuang Lu ◽

Panos Hatsis ◽

Cicely Berg ◽

Frank W. Lee ◽

Suresh K. Balani

Keyword(s):

Cytochrome P450 ◽

Drug Interactions ◽

Human Hepatocyte ◽

Phenotypic Data ◽

Hepatocyte Suspension ◽

Pharmacokinetic Drug

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Oral Terbinafine: A New Antifungal Agent

Annals of Pharmacotherapy ◽

10.1177/106002809703100412 ◽

1997 ◽

Vol 31 (4) ◽

pp. 445-456 ◽

Cited By ~ 58

Author(s):

Susan M Abdel-Rahman ◽

Milap C Nahata

Keyword(s):

Adverse Effects ◽

Drug Interactions ◽

Fungal Infections ◽

Case Reports ◽

Current Standard ◽

Open Label ◽

Double Blind ◽

Pathogenic Yeast

Objective To review the pharmacology, pharmacokinetics, efficacy, adverse effects, drug interactions, and dosage guidelines of terbinafine. Available comparative data of terbinafine and other antimycotic agents are described for understanding the potential role of terbinafine in patient care. Data Sources A MEDLINE search restricted to English language during 1966–1996 and extensive review of journals was conducted to prepare this article. MeSH headings included allylamines, terbinafine, SF 86–327, dermatophytosis, dermatomycosis. Data Extraction The data on pharmacokinetics, adverse effects, and drug interactions were obtained from open-label and controlled studies and case reports. Controlled single- or double-blind studies were evaluated to describe the efficacy of terbinafine in the treatment of various fungal infections. Data Synthesis Terbinafine is the first oral antimycotic in the allylamines class: a fungicidal agent that inhibits ergosterol synthesis at the stage of squalene epoxidation. Terbinafine demonstrates excellent in vitro activity against the majority of dermatophyte species including Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum; less activity is seen against Dematiaceae and the filamentous fungi. It is least active against the pathogenic yeast and this correlates with the relatively poor efficacy against these organisms in vivo. High concentrations of terbinafine are achieved in keratinous tissues, the site of superficial infections, and these concentrations are maintained for up to 3 months. The clinical efficacy of terbinafine against a number of dermatophyte infections exceeds that of the current standard of therapy, griseofulvin. The efficacy of terbinafine may be as good or better than that of the azole antifungals. Additional studies are required to confirm these observations. Terbinafine demonstrates a good safety profile, and relatively few drug interactions have been identified. Conclusions Terbinafine is more effective than the gold standard, griseofulvin, in the treatment of tinea pedis and tinea unguinum, with considerably shorter treatment duration in the latter. It has been proven as effective as griseofulvin in the treatment of tinea capitis, tinea corporis, and tinea cruris. Terbinafine does not appear to offer any advantage in the treatment of nondermatophyte infections; its utility in the treatment of systemic infections has yet to be established. Depending on individual institutional costs, terbinafine may be a front-line drug for some superficial infections responding poorly to the current standard of therapy.

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In Vitro/In Vivo Correlation for Drug–Drug Interactions

Drug Discovery and Evaluation: Methods in Clinical Pharmacology ◽

10.1007/978-3-540-89891-7_14 ◽

2011 ◽

pp. 133-160 ◽

Cited By ~ 2

Author(s):

Xavier Boulenc ◽

Wolfgang Schmider ◽

Olivier Barberan

Keyword(s):

Drug Interactions

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Model-Informed Drug Discovery and Development Strategy for the Rapid Development of Anti-Tuberculosis Drug Combinations

Applied Sciences ◽

10.3390/app10072376 ◽

2020 ◽

Vol 10 (7) ◽

pp. 2376 ◽

Cited By ~ 3

Author(s):

Rob C. van Wijk ◽

Rami Ayoun Alsoud ◽

Hans Lennernäs ◽

Ulrika S. H. Simonsson

Keyword(s):

Drug Discovery ◽

Drug Interactions ◽

Development Strategy ◽

Drug Exposure ◽

Rapid Development ◽

Drug Combinations ◽

Pharmacodynamic Modeling ◽

Drug Discovery And Development

The increasing emergence of drug-resistant tuberculosis requires new effective and safe drug regimens. However, drug discovery and development are challenging, lengthy and costly. The framework of model-informed drug discovery and development (MID3) is proposed to be applied throughout the preclinical to clinical phases to provide an informative prediction of drug exposure and efficacy in humans in order to select novel anti-tuberculosis drug combinations. The MID3 includes pharmacokinetic-pharmacodynamic and quantitative systems pharmacology models, machine learning and artificial intelligence, which integrates all the available knowledge related to disease and the compounds. A translational in vitro-in vivo link throughout modeling and simulation is crucial to optimize the selection of regimens with the highest probability of receiving approval from regulatory authorities. In vitro-in vivo correlation (IVIVC) and physiologically-based pharmacokinetic modeling provide powerful tools to predict pharmacokinetic drug-drug interactions based on preclinical information. Mechanistic or semi-mechanistic pharmacokinetic-pharmacodynamic models have been successfully applied to predict the clinical exposure-response profile for anti-tuberculosis drugs using preclinical data. Potential pharmacodynamic drug-drug interactions can be predicted from in vitro data through IVIVC and pharmacokinetic-pharmacodynamic modeling accounting for translational factors. It is essential for academic and industrial drug developers to collaborate across disciplines to realize the huge potential of MID3.

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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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In Vitro/In Vivo Correlation for Drug-Drug Interactions

Drug Discovery and Evaluation: Methods in Clinical Pharmacology ◽

10.1007/978-3-319-56637-5_14-1 ◽

2017 ◽

pp. 1-20

Author(s):

Jan Wahlstrom ◽

Larry Wienkers

Keyword(s):

Drug Interactions

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A sensitive HPLC-FL method to simultaneously determine febuxostat and diclofenac in rat plasma: assessment of metabolic drug interactions in vitro and in vivo

Analytical Methods ◽

10.1039/d0ay00471e ◽

2020 ◽

Vol 12 (16) ◽

pp. 2166-2175 ◽

Cited By ~ 1

Author(s):

Dong-Gyun Han ◽

Kyu-Sang Kim ◽

Seong-Wook Seo ◽

Young Mee Baek ◽

Yunjin Jung ◽

...

Keyword(s):

Sample Preparation ◽

Drug Interactions ◽

Simultaneous Determination ◽

Small Volume ◽

Rat Plasma ◽

Metabolic Drug ◽

Simple Sample Preparation

We developed a sensitive, simple and validated HPLC-FL method for simultaneous determination of FEB and DIC in rat plasma. The method requires a relatively small volume of sample, has simple sample preparation and excellent sensitivity.

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