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Keywords = presystemic drug–drug interactions

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32 pages, 4982 KiB  
Article
Involvement of Transporters in Intestinal Drug–Drug Interactions of Oral Targeted Anticancer Drugs Assessed by Changes in Drug Absorption Time
by David Malnoë, Olivier Fardel and Pascal Le Corre
Pharmaceutics 2022, 14(11), 2493; https://doi.org/10.3390/pharmaceutics14112493 - 17 Nov 2022
Cited by 7 | Viewed by 2376
Abstract
(1) Background: Oral targeted anticancer drugs are victims of presystemic pharmacokinetic drug–drug interactions (DDI). Identification of the nature of these DDIs, i.e., enzyme-based or/and transporter-based, is challenging, since most of these drugs are substrates of intestinal and/or hepatic cytochrome P-450 enzymes and of [...] Read more.
(1) Background: Oral targeted anticancer drugs are victims of presystemic pharmacokinetic drug–drug interactions (DDI). Identification of the nature of these DDIs, i.e., enzyme-based or/and transporter-based, is challenging, since most of these drugs are substrates of intestinal and/or hepatic cytochrome P-450 enzymes and of intestinal membrane transporters. (2) Methods: Variations in mean absorption time (MAT) between DDIs and control period (MAT ratios < 0.77 or >1.30) have been proposed to implicate transporters in DDIs at the intestinal level. This methodology has been applied to a large set of oral targeted anticancer drugs (n = 54, involved in 77 DDI studies), from DDI studies available either in the international literature and/or in publicly accessible FDA files. (3) Results: Significant variations in MAT were evidenced in 33 DDI studies, 12 of which could be explained by modulation of an efflux transporter. In 21 DDI studies, modulation of efflux transporters could not explain the MAT variation, suggesting a possible relevant role of influx transporters in the intestinal absorption. (4) Conclusions: This methodology allows one to suggest the involvement of intestinal transporters in DDIs, and should be used in conjunction with in vitro methodologies to help understanding the origin of DDIs. Full article
(This article belongs to the Special Issue Drug Metabolism/Transport and Pharmacokinetics, Volume II)
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21 pages, 3957 KiB  
Review
Pharmaceutical Excipients and Drug Metabolism: A Mini-Review
by Rahul Patel, James Barker and Amr ElShaer
Int. J. Mol. Sci. 2020, 21(21), 8224; https://doi.org/10.3390/ijms21218224 - 3 Nov 2020
Cited by 72 | Viewed by 12525
Abstract
Conclusions from previously reported articles have revealed that many commonly used pharmaceutical excipients, known to be pharmacologically inert, show effects on drug transporters and/or metabolic enzymes. Thus, the pharmacokinetics (absorption, distribution, metabolism and elimination) of active pharmaceutical ingredients are possibly altered because of [...] Read more.
Conclusions from previously reported articles have revealed that many commonly used pharmaceutical excipients, known to be pharmacologically inert, show effects on drug transporters and/or metabolic enzymes. Thus, the pharmacokinetics (absorption, distribution, metabolism and elimination) of active pharmaceutical ingredients are possibly altered because of their transport and metabolism modulation from the incorporated excipients. The aim of this review is to present studies on the interaction of various commonly-used excipients on pre-systemic metabolism by CYP450 enzymes. Excipients such as surfactants, polymers, fatty acids and solvents are discussed. Based on all the reported outcomes, the most potent inhibitors were found to be surfactants and the least effective were organic solvents. However, there are many factors that can influence the inhibition of CYP450, for instance type of excipient, concentration of excipient, type of CYP450 isoenzyme, incubation condition, etc. Such evidence will be very useful in dosage form design, so that the right formulation can be designed to maximize drug bioavailability, especially for poorly bioavailable drugs. Full article
(This article belongs to the Special Issue Advance in Drug-Drug Interactions)
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16 pages, 3111 KiB  
Article
Inhibitory Effects of Quercetin and Its Main Methyl, Sulfate, and Glucuronic Acid Conjugates on Cytochrome P450 Enzymes, and on OATP, BCRP and MRP2 Transporters
by Violetta Mohos, Eszter Fliszár-Nyúl, Orsolya Ungvári, Katalin Kuffa, Paul W. Needs, Paul A. Kroon, Ágnes Telbisz, Csilla Özvegy-Laczka and Miklós Poór
Nutrients 2020, 12(8), 2306; https://doi.org/10.3390/nu12082306 - 31 Jul 2020
Cited by 60 | Viewed by 7098
Abstract
Quercetin is a flavonoid, its glycosides and aglycone are found in significant amounts in several plants and dietary supplements. Because of the high presystemic biotransformation of quercetin, mainly its conjugates appear in circulation. As has been reported in previous studies, quercetin can interact [...] Read more.
Quercetin is a flavonoid, its glycosides and aglycone are found in significant amounts in several plants and dietary supplements. Because of the high presystemic biotransformation of quercetin, mainly its conjugates appear in circulation. As has been reported in previous studies, quercetin can interact with several proteins of pharmacokinetic importance. However, the interactions of its metabolites with biotransformation enzymes and drug transporters have barely been examined. In this study, the inhibitory effects of quercetin and its most relevant methyl, sulfate, and glucuronide metabolites were tested on cytochrome P450 (CYP) (2C19, 3A4, and 2D6) enzymes as well as on organic anion-transporting polypeptides (OATPs) (OATP1A2, OATP1B1, OATP1B3, and OATP2B1) and ATP (adenosine triphosphate) Binding Cassette (ABC) (BCRP and MRP2) transporters. Quercetin and its metabolites (quercetin-3′-sulfate, quercetin-3-glucuronide, isorhamnetin, and isorhamnetin-3-glucuronide) showed weak inhibitory effects on CYP2C19 and 3A4, while they did not affect CYP2D6 activity. Some of the flavonoids caused weak inhibition of OATP1A2 and MRP2. However, most of the compounds tested proved to be strong inhibitors of OATP1B1, OATP1B3, OATP2B1, and BCRP. Our data demonstrate that not only quercetin but some of its conjugates, can also interact with CYP enzymes and drug transporters. Therefore, high intake of quercetin may interfere with the pharmacokinetics of drugs. Full article
(This article belongs to the Special Issue Dietary (Poly)Phenols and Health)
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