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Murakami, Teruo; Bodor, Erik; Bodor, Nicholas
doi: 10.1080/17425255.2023.2203857pmid: 37057922
Introduction Berberine (BBR), a quaternary ammonium isoquinoline alkaloid, is a substrate for P-glycoprotein (P-gp) and cytochrome P450s (CYPs). BBR exhibits a wide variety of pharmacological activities; however, its clinical application is limited due to low oral bioavailability. Areas covered Physicochemical and pharmacokinetic properties of BBR and its lipophilic metabolites, berberrubine (BRB) and dihydroberberine (DHBBR), were reviewed including solubility/lipophilicity, salt/ion-pair formation, oral bioavailability, first-pass metabolism, and intestinal microbiota-mediated metabolism, by searching research articles using PubMed. Expert opinion Pharmacokinetic analysis of BBR bioavailability data in rats revealed that the oral bioavailability is limited by the extensive CYPs-mediated intestinal first-pass metabolism, insufficient membrane permeability due to the low solubility and P-gp-mediated efflux transport, and the hepatic first-pass metabolism. Various active metabolites are generated by intestinal first-pass metabolism. Intestinal microbiota also contributes to the BBR metabolism and generates lipophilic metabolites; BRB, an active metabolite, and DHBBR, a precursor that can distribute to the brain. The pharmacokinetic analysis of BBR bioavailability data can provide a clue to developing effective dosage routes and/or formulations that can increase the oral bioavailability of BBR.
Murakami, Teruo; Bodor, Erik; Bodor, Nicholas
doi: 10.1080/17425255.2023.2203858pmid: 37060323
Introduction Berberine (BBR) possesses a wide variety of pharmacological activities. However, the oral bioavailability of BBR is low due to extensive intestinal first-pass metabolism by cytochrome P450s (CYPs), insufficient absorption due to low solubility and P-glycoprotein (P-gp)-mediated efflux transport, and hepatic first-pass metabolism in rats. Areas covered Various dosage formulations were developed to increase the oral bioavailability of BBR by overcoming the reducing factors. This article provides the developing strategy of oral dosage formulations of BBR based on the physicochemical (low solubility, formation of salts/ion-pair complex) and pharmacokinetic properties (substrate of P-gp/CYPs, extensive intestinal first-pass metabolism). Literature was searched using PubMed. Expert opinion Here, formulations increasing the dissolution rates/solubility; formulations containing a P-gp inhibitor; formulations containing solubilizer exhibiting P-gp and/or CYPs inhibitors; formulations containing absorption enhancers; gastro/duodenal retentive formulations; lipid-based formulations; formulations targeting lymphatic transport; and physicochemical modifications increasing lipophilicity were reviewed. Among these formulations, formulations that can reduce intestinal first-pass metabolisms such as formulations containing CYPs inhibitor(s) and formulations containing absorption enhancer(s) significantly increased the oral bioavailability of BBR. Further studies on other dosing routes that can avoid first-pass metabolism such as the rectal route would also be important to increase the bioavailability of BBR.
doi: 10.1080/17425255.2023.2202813pmid: 37070463
Introduction Membrane transporters are now widely recognized for their role in the absorption, distribution, clearance, and elimination of drugs. The organic cation transporters (OCTs, SLC22A) are expressed in the intestine, liver, and kidneys and are of importance in determining systemic pharmacokinetics (PK) and tissue-specific exposure of drugs and metabolites. Areas covered An overview of the role of OCTs in drug disposition is presented. Genetic variation in OCTs and the effects on PK and drug response were discussed. Expert opinion Clinical studies demonstrated significance of OCT1 and OCT2 in the hepatic uptake and renal secretion of drug, respectively. These mechanisms are important in determining the systemic PK and tissue exposure and thus pharmacodynamics of several drugs (e.g. metformin, morphine, sumatriptan). Emerging pharmacogenomic data also suggests multidrug and toxin extrusion pump (MATE1, SLC47A1) contribution to PK and response of drugs like metformin and cisplatin. Considerations to genotyping of functional and common variants of OCTs should be given, particularly for cationic drugs with hepatic elimination or renal secretion being major clearance pathways, in the clinical development. While the current evidence indicate that pharmacokinetic variability associated with known genotypes of OCTs/MATEs is relatively small, they may be of relevance in the tissue-specific effects and for drugs with low therapeutic index.
Biswas, Mohitosh; Shobana, John; Jinda, Pimonpan; Sukasem, Chonlaphat
doi: 10.1080/17425255.2023.2203860pmid: 37089014
Introduction Azole antifungal drugs are commonly prescribed to treat invasive fungal infections in various disease conditions. However, these drugs are substrates and inhibitors of cytochrome P450 (CYP) enzymes, UGT1A4, and P-gp. The genetic variants of CYP3A4/5, CYP2C9, CYP2C19, ABCB1, or UGT1A4 can modify the safety or effectiveness of azole antifungals. Areas covered This review has collated the recent advances in the pharmacogenomics of azole antifungals pertaining to their metabolism and the safety or effectiveness of their use. A literature search was performed in PubMed from inception to the 5th of December 2022 to retrieve articles focusing on pharmacogenomics of azole antifungals. Expert opinion Optimizing the safety or effectiveness of most azole antifungals, excluding voriconazole, through pharmacogenomics remains largely theoretical, pending laboratory assessment in future studies. However, the ample evidence of the clinically significant pharmacogenetic impacts of voriconazole, due to the CYP2C19 genetic variability, favors clinical implementation. The inconsistencies of the pharmacogenomics-based dosing guidelines for voriconazole, from different international pharmacogenomics working groups, may hinder clinicians in assimilating and applying such pharmacogenetic information into clinical practice. Consideration of drug–drug interactions along with the pharmacogenetic effects may advance the precision medicine of azole antifungals and allow greater effectiveness in clinical practice.
Petrović, Sanja; Kovačević, Milena; Vezmar Kovačević, Sandra; Miljkovic, Branislava
doi: 10.1080/17425255.2023.2203859pmid: 37071502
Background Data on drug-induced liver injury (DILI) caused by newer antiseizure medications (ASMs) in the elderly are scarce and mainly come from literature case reports. We analyzed Individual Case Safety Reports (ICSRs) of DILI in elderly patients treated with newer ASMs reported to VigiBase. Research design and methods Empirica™ Signal software was used to retrieve ICSRs reported to VigiBase up to 31 December 2021 and to calculate Empirical Bayesian Geometric Mean and corresponding 90% confidence intervals (EB05, EB95) for each drug-event pair. EB05 > 2, N > 0 was considered a signal. Analysis by age subgroups and gender was performed to assess the influence of these factors on ICSR characteristics and identified signals. Results There were 1399 ICSRs reporting 1947 events of hepatotoxicity. 56.97% of the reports were reported in females, 67.05% were serious, and 3.36% resulted in death. For one or more events of hepatotoxicity, signals were detected for lamotrigine, levetiracetam, oxcarbazepine, topiramate, and zonisamide. Age- and gender-biased reporting frequency was identified for topiramate-induced hyperammonemia, with disproportionally higher reporting frequency in ≥75-year-old male patients. Conclusions The results of our study indicate differences among newer ASMs in their potential to cause DILI in the elderly. Further studies are needed to confirm the associations identified in this study.
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