Predicting in vivo drug interactions from in vitro drug discovery data

Wienkers, Larry C.; Heath, Timothy G.

doi:10.1038/nrd1851

Cited by 787 publications

(603 citation statements)

References 78 publications

Supporting

Mentioning

591

Contrasting

Unclassified

Order By: Relevance

“…Competitive inhibition, which was demonstrated by caffeic acid and p‐coumaric acid towards cotinine formation, is characterized by reversible binding of the inhibitor to the substrate‐binding site, with the potential for this inhibition to be overcome by high concentrations of the substrate (i.e . nicotine) 36. Quercetin exhibited characteristics of a mixed inhibitor, suggesting that this compound binds to the vacant, or already substrate‐bound, enzyme with greater affinity for one state or the other 37.…”

Section: Discussionmentioning

confidence: 99%

Does coffee consumption impact on heaviness of smoking?

et al. 2017

View full text Add to dashboard Cite

Background and AimsCoffee consumption and cigarette smoking are strongly associated, but whether this association is causal remains unclear. We sought to: (1) determine whether coffee consumption influences cigarette smoking causally, (2) estimate the magnitude of any association and (3) explore potential mechanisms.DesignWe used Mendelian randomization (MR) analyses of observational data, using publicly available summarized data from the Tobacco and Genetics (TAG) consortium, individual‐level data from the UK Biobank and in‐vitro experiments of candidate compounds.SettingThe TAG consortium includes data from studies in several countries. The UK Biobank includes data from men and women recruited across England, Wales and Scotland.ParticipantsThe TAG consortium provided data on n ≤ 38 181 participants. The UK Biobank provided data on 8072 participants.MeasurementsIn MR analyses, the exposure was coffee consumption (cups/day) and the outcome was heaviness of smoking (cigarettes/day). In our in‐vitro experiments we assessed the effect of caffeic acid, quercetin and p‐coumaric acid on the rate of nicotine metabolism in human liver microsomes and cDNA‐expressed human CYP2A6.FindingsTwo‐sample MR analyses of TAG consortium data indicated that heavier coffee consumption might lead to reduced heaviness of smoking [beta = −1.49, 95% confidence interval (CI) = −2.88 to −0.09]. However, in‐vitro experiments found that the compounds investigated are unlikely to inhibit significantly the rate of nicotine metabolism following coffee consumption. Further MR analyses in UK Biobank found no evidence of a causal relationship between coffee consumption and heaviness of smoking (beta = 0.20, 95% CI = –1.72 to 2.12).ConclusionsAmount of coffee consumption is unlikely to have a major causal impact upon amount of cigarette smoking. If it does influence smoking, this is not likely to operate via effects of caffeic acid, quercetin or p‐coumaric acid on nicotine metabolism. The observational association between coffee consumption and cigarette smoking may be due to smoking impacting on coffee consumption or confounding.

show abstract

Section: Discussionmentioning

confidence: 99%

Does coffee consumption impact on heaviness of smoking?

et al. 2017

View full text Add to dashboard Cite

show abstract

“…5) It is estimated that CYP enzymes are responsible for the metabolism of approximately three-quarters of the most prescribed drugs that are cleared by metabolism, including antiretroviral agents used to treat HIV. [6][7][8] Unwanted drug-drug interactions often result from the inhibition or induction of one or more CYP isoforms by a first drug, resulting in increased or decreased exposure, respectively, of a second drug that is metabolized by the same isoforms. 9,10) Unintended alterations in the exposure to drugs or their metabolites may have significant effects including increased toxicities or therapeutic failure.…”

mentioning

confidence: 99%

Delamanid Does Not Inhibit or Induce Cytochrome P450 Enzymes <i>in Vitro</i>

Shimokawa

Sasahara

Yoda

et al. 2014

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Delamanid is a new drug for the treatment of multidrug-resistant tuberculosis. Individuals who are coinfected with human immunodeficiency virus and Mycobacterium tuberculosis may require treatment with a number of medications that might interact significantly with the CYP enzyme system as inhibitors or inducers. It is therefore important to understand how drugs in development for the treatment of tuberculosis will affect CYP enzyme metabolism. The ability of delamanid to inhibit or induce CYP enzymes was investigated in vitro using human liver microsomes or human hepatocytes. Delamanid (100 µM) had little potential for mechanism-based inactivation on eight CYP isoforms (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4). Delamanid's metabolites were noted to inhibit the metabolism of some CYP isoforms, but these effects were observed only at metabolite concentrations that were well above those observed in human plasma during clinical trials. Delamanid (≤10 µM) did not induce CYP1A2, CYP2C9, and CYP3A4 activities in human hepatocytes, and there were no increases in CYP1A2, CYP2B6, CYP2C9, and CYP3A4 mRNA levels. Taken together, these data suggest that delamanid is unlikely to cause clinically relevant drug-drug interactions when co-administered with products that are metabolized by the CYP enzyme system.

show abstract

“…Because no significant inhibition of P450 was observed, and based on the low plasma concentration of compound 5 observed (i.e., 2-8 ng/ml; Table 1) it is unlikely that compound 5 inhibits P450 and alcohol metabolism in vivo at the doses used in this study. This is based on the well recognized relationship (i.e., I/K i ) that predicts the potential for in vivo interactions (Wienkers and Heath, 2005). If I/K i is greater than 1, then a significant interaction is predicted.…”

Section: Resultsmentioning

confidence: 99%

Potent Inhibition of Alcohol Self-Administration in Alcohol-Preferring Rats by aκ-Opioid Receptor Antagonist

Cashman

Azar

2014

J Pharmacol Exp Ther

View full text Add to dashboard Cite

A substituted aryl amide derivative of 6-naltrexamine-17-cyclopropylmethyl-3,14b-dihydroxy-4,5a-epoxy-6b-[(49-trimethylfluoro) benzamido]morphinan-hydrochloride-(compound 5), previously shown to be a potent k-opioid receptor antagonist, was used to characterize the physicochemical properties and efficacy to decrease alcohol self-administration in alcohol-preferring rats (P-rats) and binge-like P-rats. Previous studies showed that compounds closely related to compound 5 possessed favorable properties regarding penetration of the blood-brain barrier. Pharmacokinetic studies showed that compound 5 had acceptable bioavailability. In contrast to other k-receptor antagonists, in particular norbinaltorphimine, compound 5 showed favorable drug-like properties. Based on these findings, further studies were done. Safety studies showed that compound 5 was not hepatotoxic at doses 200-fold greater than an efficacious dose.The effects of compound 5 or naltrexone on the hepatotoxicity of thiobenzamide were investigated. In contrast to naltrexone, which exacerbated thiobenzamide-mediated hepatotoxicity, compound 5 was observed to be hepatoprotective. Based on the physicochemical properties of compound 5, the compound was examined in rat animal models of alcohol self-administration. The inhibition of ethanol self-administration by compound 5 in alcohol-dependent and alcohol-nondependent P-rats trained to self-administer a 10% (w/v) ethanol solution, using operant techniques, showed very potent efficacy (i.e., estimated ED 50 values of 4-5 mg/kg). In a binge-like P-rat animal model, inhibition of alcohol self-administration by compound 5 had an estimated ED 50 value of 8 mg/kg. The results suggest that compound 5 is a potent drug-like k-opioid receptor antagonist of utility in alcohol cessation medications development.

show abstract

Predicting in vivo drug interactions from in vitro drug discovery data

Cited by 787 publications

References 78 publications

Does coffee consumption impact on heaviness of smoking?

Does coffee consumption impact on heaviness of smoking?

Delamanid Does Not Inhibit or Induce Cytochrome P450 Enzymes <i>in Vitro</i>

Potent Inhibition of Alcohol Self-Administration in Alcohol-Preferring Rats by aκ-Opioid Receptor Antagonist

Contact Info

Product

Resources

About