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

ABSTRACTMacrolactin A (MA) and 7-O-succinyl macrolactin A (SMA), polyene macrolides containing a 24-membered lactone ring, show antibiotic effects superior to those of teicoplanin against vancomycin-resistant enterococci and methicillin-resistantStaphylococcus aureus. MA and SMA are currently being evaluated as antitumor agents in preclinical studies in Korea. We evaluated the potential of MA and SMA for the inhibition or induction of human liver cytochrome P450 (CYP) enzymes and UDP-glucuronosyltransferases (UGTs)in vitroto assess their safety as new molecular entities. We demonstrated that MA and SMA are potent competitive inhibitors of CYP2C9, withKivalues of 4.06 μM and 10.6 μM, respectively. MA and SMA also weakly inhibited UGT1A1 activity, withKivalues of 40.1 μM and 65.3 μM, respectively. However, these macrolactins showed no time-dependent inactivation of the nine CYPs studied. In addition, MA and SMA did not induce CYP1A2, CYP2B6, or CYP3A4/5. On the basis of anin vitro-in vivoextrapolation, our data strongly suggested that MA and SMA are unlikely to cause clinically significant drug-drug interactions mediated via inhibition or induction of most of the CYPs involved in drug metabolismin vivo, except for the inhibition of CYP2C9 by MA. Similarly, MA and SMA are unlikely to inhibit the activity of UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7 enzymesin vivo. Although further investigations will be required to clarify thein vivointeractions of MA with CYP2C9-targeted drugs, our findings offer a clearer understanding and prediction of drug-drug interactions for the safe use of MA and SMA in clinical practice.

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Carboxymefloquine, the Major Metabolite of the Antimalarial Drug Mefloquine, Induces Drug-Metabolizing Enzyme and Transporter Expression by Activation of Pregnane X Receptor

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04140-14 ◽

2014 ◽

Vol 59 (1) ◽

pp. 96-104 ◽

Cited By ~ 11

Author(s):

Rita Piedade ◽

Stefanie Traub ◽

Andreas Bitter ◽

Andreas K. Nüssler ◽

José P. Gil ◽

...

Keyword(s):

Drug Interactions ◽

Antimalarial Drug ◽

Pregnane X Receptor ◽

Antimalarial Drugs ◽

Drug Metabolites ◽

Protein Levels ◽

Two Hybrid ◽

Pharmacokinetic Drug

ABSTRACTMalaria patients are frequently coinfected with HIV and mycobacteria causing tuberculosis, which increases the use of coadministered drugs and thereby enhances the risk of pharmacokinetic drug-drug interactions. Activation of the pregnane X receptor (PXR) by xenobiotics, which include many drugs, induces drug metabolism and transport, thereby resulting in possible attenuation or loss of the therapeutic responses to the drugs being coadministered. While several artemisinin-type antimalarial drugs have been shown to activate PXR, data on nonartemisinin-type antimalarials are still missing. Therefore, this study aimed to elucidate the potential of nonartemisinin antimalarial drugs and drug metabolites to activate PXR. We screened 16 clinically used antimalarial drugs and six major drug metabolites for binding to PXR using the two-hybrid PXR ligand binding domain assembly assay; this identified carboxymefloquine, the major and pharmacologically inactive metabolite of the antimalarial drug mefloquine, as a potential PXR ligand. Two-hybrid PXR-coactivator and -corepressor interaction assays and PXR-dependent promoter reporter gene assays confirmed carboxymefloquine to be a novel PXR agonist which specifically activated the human receptor. In the PXR-expressing intestinal LS174T cells and in primary human hepatocytes, carboxymefloquine induced the expression of drug-metabolizing enzymes and transporters on the mRNA and protein levels. The crucial role of PXR for the carboxymefloquine-dependent induction of gene expression was confirmed by small interfering RNA (siRNA)-mediated knockdown of the receptor. Thus, the clinical use of mefloquine may result in pharmacokinetic drug-drug interactions by means of its metabolite carboxymefloquine. Whether thesein vitrofindings are ofin vivorelevance has to be addressed in future clinical drug-drug interaction studies.

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Does In Vitro Cytochrome P450 Downregulation Translate to In Vivo Drug‐Drug Interactions? Preclinical and Clinical Studies With 13‐ cis ‐Retinoic Acid

Clinical and Translational Science ◽

10.1111/cts.12616 ◽

2019 ◽

Vol 12 (4) ◽

pp. 350-360 ◽

Cited By ~ 4

Author(s):

Faith Stevison ◽

Mika Kosaka ◽

Jane R. Kenny ◽

Susan Wong ◽

Cathryn Hogarth ◽

...

Keyword(s):

Cytochrome P450 ◽

Retinoic Acid ◽

Drug Interactions ◽

Clinical Studies ◽

Preclinical And Clinical Studies

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In vitro and in vivo methods to assess pharmacokinetic drug– drug interactions in drug discovery and development

Biopharmaceutics & Drug Disposition ◽

10.1002/bdd.2212 ◽

2020 ◽

Vol 41 (1-2) ◽

pp. 3-31 ◽

Cited By ~ 4

Author(s):

Chuang Lu ◽

Li Di

Keyword(s):

Drug Discovery ◽

Drug Interactions ◽

Drug Discovery And Development ◽

Pharmacokinetic Drug

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Evaluation of Pharmacokinetic Drug–Drug Interactions: A Review of the Mechanisms, In Vitro and In Silico Approaches

Metabolites ◽

10.3390/metabo11020075 ◽

2021 ◽

Vol 11 (2) ◽

pp. 75

Author(s):

Yaru Peng ◽

Zeneng Cheng ◽

Feifan Xie

Keyword(s):

Drug Interactions ◽

In Silico ◽

Drug Efficacy ◽

Primary Concern ◽

Factors Affecting ◽

Pbpk Models ◽

Drug Concentrations ◽

Pharmacokinetic Drug

Pharmacokinetic drug–drug interactions (DDIs) occur when a drug alters the absorption, transport, distribution, metabolism or excretion of a co-administered agent. The occurrence of pharmacokinetic DDIs may result in the increase or the decrease of drug concentrations, which can significantly affect the drug efficacy and safety in patients. Enzyme-mediated DDIs are of primary concern, while the transporter-mediated DDIs are less understood but also important. In this review, we presented an overview of the different mechanisms leading to DDIs, the in vitro experimental tools for capturing the factors affecting DDIs, and in silico methods for quantitative predictions of DDIs. We also emphasized the power and strategy of physiologically based pharmacokinetic (PBPK) models for the assessment of DDIs, which can integrate relevant in vitro data to simulate potential drug interaction in vivo. Lastly, we pointed out the future directions and challenges for the evaluation of pharmacokinetic DDIs.

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