Pharmacokinetic Drug–Drug Interactions among Antiepileptic Drugs, Including CBD, Drugs Used to Treat COVID-19 and Nutrients

Anti-epileptic drugs (AEDs) are an important group of drugs of several generations, ranging from the oldest phenobarbital (1912) to the most recent cenobamate (2019). Cannabidiol (CBD) is increasingly used to treat epilepsy. The outbreak of the SARS-CoV-2 pandemic in 2019 created new challenges in the effective treatment of epilepsy in COVID-19 patients. The purpose of this review is to present data from the last few years on drug–drug interactions among of AEDs, as well as AEDs with other drugs, nutrients and food. Literature data was collected mainly in PubMed, as well as google base. The most important pharmacokinetic parameters of the chosen 29 AEDs, mechanism of action and clinical application, as well as their biotransformation, are presented. We pay a special attention to the new potential interactions of the applied first-generation AEDs (carbamazepine, oxcarbazepine, phenytoin, phenobarbital and primidone), on decreased concentration of some medications (atazanavir and remdesivir), or their compositions (darunavir/cobicistat and lopinavir/ritonavir) used in the treatment of COVID-19 patients. CBD interactions with AEDs are clearly defined. In addition, nutrients, as well as diet, cause changes in pharmacokinetics of some AEDs. The understanding of the pharmacokinetic interactions of the AEDs seems to be important in effective management of epilepsy.

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The Development and Validation of a Novel “Dual Cocktail” Probe for Cytochrome P450s and Transporter Functions to Evaluate Pharmacokinetic Drug-Drug and Herb-Drug Interactions

Pharmaceutics ◽

10.3390/pharmaceutics12100938 ◽

2020 ◽

Vol 12 (10) ◽

pp. 938

Author(s):

Mihwa Kwon ◽

Ji-Hyeon Jeon ◽

Min-Koo Choi ◽

Im-Sook Song

Keyword(s):

Drug Interactions ◽

Plasma Concentrations ◽

Pharmacokinetic Parameters ◽

Evaluation Protocol ◽

Pharmacokinetic Properties ◽

Comparison Groups ◽

Cyp Isoforms ◽

Development And Validation ◽

Oral Doses ◽

Pharmacokinetic Drug

This study was designed to develop and validate a 10 probe drug cocktail named “Dual Cocktail”, composed of caffeine (Cyp1a2 in rat and CYP1A2 in human, 1 mg/kg), diclofenac (Cyp2c11 in rat and CYP2C9 in human, 2 mg/kg), omeprazole (Cyp2c11 in rat and CYP2C19 in human, 2 mg/kg), dextromethorphan (Cyp2d2 in rat and CYP2D6 in human, 10 mg/kg), nifedipine (Cyp3a1 in rat and CYP3A4 in human, 0.5 mg/kg), metformin (Oct1/2 in rat and OCT1/2 in human, 0.5 mg/kg), furosemide (Oat1/3 in rat and OAT1/3 in human, 0.1 mg/kg), valsartan (Oatp2 in rat and OATP1B1/1B3 in human, 0.2 mg/kg), digoxin (P-gp in rat and human, 2 mg/kg), and methotrexate (Mrp2 in rat and MRP2 in human, 0.5 mg/kg), for the evaluation of pharmacokinetic drug–drug and herb-drug interactions through the modulation of a representative panel of CYP enzymes or transporters in rats. To ensure no interaction among the ten probe substrates, we developed a 2-step evaluation protocol. In the first step, the pharmacokinetic properties of five individual CYP probe substrates and five individual transporter substrates were compared with the pharmacokinetics of five CYP cocktail or five transporters cocktails in two groups of randomly assigned rats. Next, a pharmacokinetic comparison was conducted between the CYP or transporter cocktail group and the dual cocktail group, respectively. None of the ten comparison groups was found to be statistically significant, indicating the CYP and transporter substrate sets or dual cocktail set could be concomitantly administered in rats. The “Dual Cocktail” was further validated by assessing the metabolism of nifedipine and omeprazole, which was significantly reduced by a single oral dose of ketoconazole (10 mg/kg); however, no changes were observed in the pharmacokinetic parameters of other probe substrates. Additionally, multiple oral doses of rifampin (20 mg/kg) reduced the plasma concentrations of nifedipine and digoxin, although not any of the other substrates. In conclusion, the dual cocktail can be used to characterize potential pharmacokinetic drug–drug interactions by simultaneously monitoring the activity of multiple CYP isoforms and transporters.

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A review of pharmacokinetic and pharmacodynamic interactions with antipsychotics

Mental Health Clinician ◽

10.9740/mhc.2016.01.021 ◽

2016 ◽

Vol 6 (1) ◽

pp. 21-27 ◽

Cited By ~ 2

Author(s):

Ruki Wijesinghe

Keyword(s):

Drug Interactions ◽

First Generation ◽

Antipsychotic Drugs ◽

Relevant Literature ◽

Treatment Interventions ◽

Pharmacodynamic Interactions ◽

Common Drug ◽

Second Generation Antipsychotics ◽

Clinically Significant ◽

Potential Interactions

Abstract Introduction Antipsychotics are widely used and often in combination with other drugs, thereby frequently subjected to drug-drug interactions. This review will provide a summary of potential pharmacokinetic (PK) and pharmacodynamic (PD) drug interactions associated with antipsychotic drugs. Methods A literature search was conducted for clinically significant drug interactions with antipsychotics. Results Most common PK drug interactions take place via the cytochrome P450 (CYP) system. PK profiles of first generation antipsychotics are inadequately studied; nevertheless most common drug interactions involve changes to their metabolic processes. Interactions with second generation antipsychotics are somewhat well-established, documented, and give some guidance for therapeutic treatment interventions. PD interactions occurring at the receptor level result in additive, synergistic, or antagonistic effects. Discussion This review summarizes a collection of relevant literature of significant PK and PD interactions occurring with antipsychotics. The involvement of multiple CYP enzymes makes it more difficult to predict the extent of the interaction and clinicians should take into consideration the timeline when evaluating potential interactions.

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Regulation of Plasma Low Density Lipoprotein Levels Biopharmacological Regulation of Protein Phosphorylation Calcium-Activated Neutral Protease Microbial Iron Transport Pharmacokinetic Drug Interactions

10.1007/978-3-642-72902-7 ◽

1987 ◽

Author(s):

W. R. Bartle ◽

V. Braun ◽

J. M. Dietschy ◽

Y. Emori ◽

M. Hagiwara ◽

...

Keyword(s):

Drug Interactions ◽

Protein Phosphorylation ◽

Iron Transport ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Neutral Protease ◽

Low Density ◽

Pharmacokinetic Drug

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Faculty Opinions recommendation of Perpetrators of pharmacokinetic drug-drug interactions arising from altered cytochrome P450 activity: a criteria-based assessment.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.10396957.11219055 ◽

2011 ◽

Author(s):

Geoffrey Tucker

Keyword(s):

Cytochrome P450 ◽

Drug Interactions ◽

Cytochrome P450 Activity ◽

P450 Activity ◽

Pharmacokinetic Drug

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Pharmacokinetic Drug-drug Interaction of Antibiotics Used in Sepsis Care in China

Current Drug Metabolism ◽

10.2174/1389200221666200929115117 ◽

2020 ◽

Vol 21 ◽

Author(s):

Xuan Yu ◽

Zixuan Chu ◽

Jian Li ◽

Rongrong He ◽

Yaya Wang ◽

...

Keyword(s):

Drug Interaction ◽

Drug Interactions ◽

Penicillin G ◽

Literature Mining ◽

Human Pharmacokinetics ◽

P450 Enzyme ◽

Drug Drug Interaction ◽

Pharmacokinetic Drug ◽

Sepsis Care

Background: Many antibiotics have a high potential for having an interaction with drugs, as perpetrator and/or victim, in critically ill patients, and particularly in sepsis patients. Methods: The aim of this review is to summarize the pharmacokinetic drug-drug interaction (DDI) of 45 antibiotics commonly used in sepsis care in China. Literature mining was conducted to obtain human pharmacokinetics/dispositions of the antibiotics, their interactions with drug metabolizing enzymes or transporters, and their associated clinical drug interactions. Potential DDI is indicated by a DDI index > 0.1 for inhibition or a treated-cell/untreated-cell ratio of enzyme activity being > 2 for induction. Results: The literature-mined information on human pharmacokinetics of the identified antibiotics and their potential drug interactions is summarized. Conclusion: Antibiotic-perpetrated drug interactions, involving P450 enzyme inhibition, have been reported for four lipophilic antibacterials (ciprofloxacin, erythromycin, trimethoprim, and trimethoprim-sulfamethoxazole) and three lipophilic antifungals (fluconazole, itraconazole, and voriconazole). In addition, seven hydrophilic antibacterials (ceftriaxone, cefamandole, piperacillin, penicillin G, amikacin, metronidazole, and linezolid) inhibit drug transporters in vitro. Despite no reported clinical PK drug interactions with the transporters, caution is advised in the use of these antibacterials. Eight hydrophilic antibacterials (all β-lactams; meropenem, cefotaxime, cefazolin, piperacillin, ticarcillin, penicillin G, ampicillin, and flucloxacillin), are potential victims of drug interactions due to transporter inhibition. Rifampin is reported to perpetrate drug interactions by inducing CYP3A or inhibiting OATP1B; it is also reported to be a victim of drug interactions, due to the dual inhibition of CYP3A4 and OATP1B by indinavir. In addition, three antifungals (caspofungin, itraconazole, and voriconazole) are reported to be victims of drug interactions because of P450 enzyme induction. Reports for other antibiotics acting as victims in drug interactions are scarce.

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