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Medicines in neonates
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
P-glycoprotein (P-gp) is normally found within the cellular membranes of the intestinal tract (duodenum, ileum, jejunum, colon), apical membrane of hepatocytes, renal proximal tubular cells and on the luminal side of the capillary endothelial cells that make up the blood brain barrier [25–27]. This efflux protein has affinity for a broad range of hydrophobic substrates and effectively “pumps” xenobiotics out of cells, influencing the amount of a drug that may be absorbed into systemic circulation, influencing the rate at which a drug may be cleared by the liver or kidney, or influence the amount of drug that enters the central nervous system [25–28]. Moreover, the degree of expression and/or modulation of P-gp activity by inhibitors or inducers are probably the basis for a number of clinically important drug-drug interactions. The variability in intestinal absorption characteristics for many drugs is likely a direct result of the variability of P-gp expression within the intestinal tract as well as the presence or absence of P-gp modulators [25,26,29].
Pharmacology of azole antifungal agents
Published in Mahmoud A. Ghannoum, John R. Perfect, Antifungal Therapy, 2019
P-glycoprotein is an ATP dependent transport protein that is found throughout the human body and is involved in the transport of many drugs. There are significant similarities in the list of agents that are substrates and inhibitors between cytochrome P450 3A4 and p-glycoprotein [84]. As a result, the azole antifungals can also inhibit p-glycoprotein and many, with the exception of voriconazole and posaconazole are also substrates [176,208]. Often it is difficult to differentiate the role of p-glycoprotein in azole-induced drug–drug interactions from that of Cyp3A4.
Ketoconazole
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
The major mechanism for the drug interactions between ketoconazole and other drugs is inhibition or activation of the mixed-function oxidase system activity of hepatic microsomal enzymes through the P450 system. Compared to other azoles, ketoconazole is the strongest inhibitor of P450 cytochrome. More specifically, it is a strong inhibitor of CYP3A4, a moderate inhibitor of CYP1A1, 1A2, 2A6, 2C9, and 2E1, and a substrate and inhibitor of p-glycoprotein (Albengres et al., 1998; Nivoix et al., 2008; Niwa et al., 2014). Ketoconazole decreases the total clearance and significantly prolongs the half-life of antipyrine in normal volunteers (D’Mello et al., 1985). In addition, ketoconazole may exert significant drug interaction via the inhibition of the multidrug efflux transporter, P-glycoprotein (Wang et al., 2002). P-glycoprotein is ubiquitously expressed within cell membranes of the gastrointestinal tract, liver, blood–brain barrier, adrenal glands, and kidneys, and limits drug uptake into the tissue (Gottesman and Pastan, 1993). It acts as an efflux pump of many drugs and may limit bioavailability of these agents.
An update on late-stage functionalization in today’s drug discovery
Published in Expert Opinion on Drug Discovery, 2023
Andrew P. Montgomery, Jack M. Joyce, Jonathan J. Danon, Michael Kassiou
To develop P-glycoprotein (P-gp) inhibitors for the treatment of multi-drug resistant cancers, Ma et al. employed a Pd(II)-catalyzed C(sp2)–H activation strategy to rapidly explore the SAR of a promising inhibitor scaffold 56 (Figure 7A). Initially, the authors attempted to functionalize 56, and conversion was achieved; however, purification was deemed too challenging. As such, the LSF was performed earlier in the synthesis, with advanced intermediate 57 used to generate a series of nine intermediates, which could be easily converted to the desired analogs of 56 (representative example shown in Figure 7A). All nine analogs demonstrated improved P-gp reversal activity over the lead scaffold 56. Of these, the chlorinated analog 58 was identified as the most potent of the series (EC50 = 37.2 ± 5.4 nM) at reversing doxorubicin (DOX) resistance in SW620/AD300 cells. As such, 58 was advanced to ABCB1-overexpressing K562/A02 mice xenograft models where tumor growth was significantly inhibited when it was co-administered with DOX, when compared to DOX alone [75].
Relugolix: A new kid on the block among gonadotrophin-releasing hormone antagonists
Published in Arab Journal of Urology, 2021
Charalampos Fragkoulis, Ioannis Glykas, Athanasios Dellis, Iraklis Mitsogiannis, Athanasios Papatsoris
A major concern regarding the use of relugolix in everyday clinical practice is the patient adherence to treatment. Although in the HERO study compliance was extremely high (99%), this may not reflect the real-life setting. Data support that food intake decreases the drug absorption by 50%, thus it should be administered on an empty stomach. Furthermore, plasma protein binding is ~70%, which may result in interactions with several inducers or inhibitors of p-glycoprotein. On the other hand, relugolix is an orally administered GnRH antagonist and that makes it a more patient friendly medicine compared with injectable depot formulae, as local site reactions are quite common in these kinds of formulae. The most important asset of relugolix over degarelix in order to encourage patient adherence is the fact that patients avoid the injection site reactions related with degarelix. Moreover, relugolix provides a more flexible dosing profile and is ideal for prompt cessation because of adverse events or intolerance. Relugolix acts as a pure GnRH antagonist, thus the concurrent administration of antiandrogen is avoided as no flare phenomenon is present.
Keeping a balance in chronic lymphocytic leukemia (CLL) patients taking ibrutinib: ibrutinib-associated adverse events and their management based on drug interactions
Published in Expert Review of Hematology, 2021
Hee Jeong Cho, Dong Won Baek, Juhyung Kim, Jung Min Lee, Joon Ho Moon, Sang Kyun Sohn
Medications that are needed for AF management commonly interact with ibrutinib. Despite the paucity of pharmacokinetic studies of ibrutinib used in conjunction with AF medication, diltiazem, verapamil, amiodarone, and dronedarone are expected to increase the plasma concentration of ibrutinib by 6- to 9-fold [37]. Amiodarone’s major metabolite was found to have a potent inhibitory effect on CYP3A4 activity and could induce high plasma levels of ibrutinib [77]. Additionally, ibrutinib may increase the concentration of the drug combination by interacting with p-glycoprotein as well as CYP3A4. P-glycoprotein is a drug transportation protein located on the cell membrane which mediates drug absorption and elimination [78]. Anticoagulants and factor Xa inhibitors such as apixaban, rivaroxaban, and edoxaban, are p-glycoprotein and CYP34A substrates; thus, ibrutinib, a p-glycoprotein inhibitor, may potentially increase the plasma level of factor Xa inhibitors [79,80]. In particular, edoxaban is minimally (< 4% of the total elimination amount) metabolized via CYP3A4, and is therefore less prone to interact with iburtinib, compared to apixaban and rivaroxaban [81]. Dabigatran, a direct thrombin inhibitor, is a p-glycoprotein substrate that does not interact with CYP3A4, and its concentration may be increased by ibrutinib’s p-glycoprotein inhibition [37].