A Review of CYP-Mediated Drug Interactions: Mechanisms and In Vitro Drug-Drug Interaction Assessment

Lee, Jonghwa; Beers, Jessica L.; Geffert, Raeanne M.; Jackson, Klarissa D.

doi:10.3390/biom14010099

Cited by 14 publications

(1 citation statement)

References 198 publications

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“…34) In preclinical safety assessments, effects of drugs on CYP induction are routinely investigated via the quantification of mRNA expression and enzyme activity. 35) However, if the test compound acts as both an inducer (for mRNA expression) and inhibitor (for enzymatic activity), enzyme activity tests can provide mixed results. For example, ritonavir, a potent peptide-like human immunodeficiency virus protease inhibitor, is reported to induce CYP3A4 mRNA and protein expression in primary human hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

Omeprazole Induces <i>CYP3A4</i> mRNA Expression but Not CYP3A4 Protein Expression in HepaRG Cells

Fujita,

Miyake,

Shao

et al. 2024

Biological & Pharmaceutical Bulletin

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Section: Discussionmentioning

confidence: 99%

Omeprazole Induces <i>CYP3A4</i> mRNA Expression but Not CYP3A4 Protein Expression in HepaRG Cells

Fujita,

Miyake,

Shao

et al. 2024

Biological & Pharmaceutical Bulletin

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Bacterial Influence on Pharmacokinetics of Tacrolimus and Sulfasalazine through Regulation of Host Metabolism

Cooper,

Bhushan

2024

Advanced Therapeutics

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The unpredictable oral bioavailability of established drugs like tacrolimus and sulfasalazine presents a significant clinical challenge. This variability can lead to either toxicity or insufficient therapeutic effect. It is known that alterations in drug transporters and metabolic enzymes influence drug bioavailability. Recent evidence suggests that the indirect metabolism by gut microbes could influence transporters and enzymes which can affect the bioavailability of oral drugs. In this study, the pharmacokinetics of tacrolimus and sulfasalazine are modeled under varying host colonic conditions induced by the bacteria E. coli Nissle 1917 and Bifidobacterium adolescentis. Insight is provided into the sensitivity of pharmacokinetics to the bacterial influence on expression of intestinal drug transporters and cytochrome p450 enzymes. Our findings demonstrate that bacterial modulation reduces tacrolimus peak blood concentration compared to healthy renal transplant patients. Conversely, bacterial presence leads to a two‐fold increase in sulfasalazine's peak plasma concentration compared to healthy subjects. These results suggest that incorporating the gut bacteria's influence on colonic transporters and enzymes can improve the explanation of pharmacokinetic variability. This approach has the potential to refine pharmacokinetic models and ultimately address the challenge of variable oral drug bioavailability.

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Phase 1 Studies to Assess Inhaled Seralutinib as a Perpetrator or a Victim of Drug‐Drug Interactions in Healthy Participants

Li,

Parsley,

Cravets

et al. 2024

Clinical Pharm in Drug Dev

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Seralutinib, an inhaled, small‐molecule tyrosine kinase inhibitor in clinical development for the treatment of pulmonary arterial hypertension (PAH), was evaluated for its potential as a perpetrator or victim of a metabolic and transporter‐based drug‐drug interactions in 2 phase 1 studies. In study 1, 24 participants received a cocktail of probe substrates: caffeine (CYP1A2), montelukast (CYP2C8), flurbiprofen (CYP2C9), midazolam (CYP3A), and pravastatin (OATP1B1/1B3), plus digoxin (P‐gp) with or without seralutinib. In study 2, 19 participants received seralutinib with/without itraconazole, a strong CYP3A inhibitor, or fosaprepitant, a weak CYP3A inhibitor. Geometric least‐squares mean ratios and 90% confidence intervals for maximum observed concentration (Cmax) and area under the plasma concentration‐time curve (AUC) were obtained. Safety was monitored throughout the studies. All adverse events were mild or moderate in severity. Seralutinib coadministration increased AUC for midazolam 3.03‐fold and caffeine 1.32‐fold. The coadministration increased digoxin Cmax 1.28‐fold. Seralutinib did not meaningfully alter Cmax and AUC for montelukast, flurbiprofen, or pravastatin. Fosaprepitant and itraconazole increased seralutinib AUC 1.08‐ and 1.84‐fold, respectively. Seralutinib is a moderate CYP3A inhibitor and a weak CYP1A2 inhibitor; it slightly inhibits P‐gp. Seralutinib exposure is minimally affected by a weak CYP3A inhibitor but is substantially increased by a strong CYP3A inhibitor.

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A Review of CYP-Mediated Drug Interactions: Mechanisms and In Vitro Drug-Drug Interaction Assessment

Cited by 14 publications

References 198 publications

Omeprazole Induces <i>CYP3A4</i> mRNA Expression but Not CYP3A4 Protein Expression in HepaRG Cells

Omeprazole Induces <i>CYP3A4</i> mRNA Expression but Not CYP3A4 Protein Expression in HepaRG Cells

Bacterial Influence on Pharmacokinetics of Tacrolimus and Sulfasalazine through Regulation of Host Metabolism

Phase 1 Studies to Assess Inhaled Seralutinib as a Perpetrator or a Victim of Drug‐Drug Interactions in Healthy Participants

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