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Pharmacology of Opioids
Published in Pamela E. Macintyre, Stephan A. Schug, Acute Pain Management, 2021
Pamela E. Macintyre, Stephan A. Schug
Codeine is metabolized in the liver, and its active metabolite is morphine. This accounts for all the analgesic effect of codeine, as the drug itself has a very low affinity for opioid receptors. It should therefore be regarded as an ineffective prodrug of morphine. Metabolism of morphine involves the enzyme CYP2D6, an isoenzyme of the cytochrome P450 system.
Immunosuppressants, rheumatic and gastrointestinal topics
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
Placebo-controlled trials using azathioprine (2.0–2.5 mg/kg/d) or 6MP (1.5 mg/kg/d) have been shown to be effective in preventing relapse in 60 to 70% of patients [23]. This has been confirmed in two paediatric studies with a better linear growth [24,25]. Determination of the active metabolite may be useful to adjust drug treatment and compliance [24].
Preclinical and Clinical Safety Assessment of Transdermal and Topical Dermatological Products
Published in Tapash K. Ghosh, Dermal Drug Delivery, 2020
Lindsey C. Yeh, Howard I. Maibach
Skin metabolism poses several potential obstacles for the transdermal delivery of beta-blockers. Skin metabolism of beta-blockers may be clinically significant if the metabolites(s) are active, toxic or irritating (Ademola et al., 1993). Active metabolites have been recovered in the skin during a program aimed at the development of a TTS for beta-blockers (Ademola et al., 1992). In addition to the difficulty to attain and maintain constant blood levels, the presence of active metabolites may pose major toxicity problems in patients with organ dysfunction (e.g., renal failure) (Ademola et al., 1992).
Angiotensin-converting enzyme inhibitor induced angioedema: not always a class effect? A case report and short narrative review
Published in Current Medical Research and Opinion, 2021
Guillaume Becker, Fabien Rougerie, Amelia-Naomi Sabo, Marie-Caroline Dalmas, Estelle Ayme-Dietrich, Laurent Monassier
From a pharmacokinetic perspective, it could be hypothesized that certain ramipril properties could lead to ACEi overexposure in this patient. Following oral administration, peak plasma concentrations of quinapril and ramipril are reached within 1 h. The extent of the absorption is approximately 60% for both drugs. Quinapril and ramipril are almost completely metabolized to the active metabolites quinaprilat and ramiprilat, respectively19,20. Both active metabolites are rapidly eliminated from the blood and distributed to tissues, including the lungs14,19,21. Both ramipril and quinapril have a high affinity for tissue ACE and a prolonged effect due to the high tissue uptake19,22. Both drugs and their active metabolites are eliminated primarily by the renal route and have relatively rapid initial elimination half-lives in plasma (quinaprilat approximately 2 h; ramiprilat 1–7 h)19,20. Their prolonged terminal phase of elimination is probably associated with the release of active substances from ACE19,23. Although the pharmacokinetics of the two drugs are quite similar, it cannot be totally excluded that differences in the elimination of quinaprilat and ramiprilat are involved in the clinical effects described in this case.
Novel synthetic treatment options for migraine
Published in Expert Opinion on Pharmacotherapy, 2021
Andrea Negro, Paolo Martelletti
Gepants represent the first class of CGRP-targeted drugs to be developed. Unfortunately, the clinical development of the first four gepants was terminated early, either because of the lack of an oral formulation or because of liver toxicity. The second generation of gepants includes rimegepant and ubrogepant, which were investigated as abortive treatment, and atogepant that is under evaluation for migraine prevention. These gepants showed a placebo-like tolerability profile and the absence of a specific pattern of side effects, which was instead identified for triptans and lasmiditan. In addition, available data show that long-term treatment is not associated with signs of hepatotoxicity. However, participants with actual cardiovascular disease were not included and the concomitant use of drugs metabolized by cytochrome P450 3A4 isoenzyme was not allowed to prevent changes in the pharmacokinetics of the tested drug [78,79]. It will be essential for future studies to investigate potential drug–drug interactions or the production of active metabolites.
Comprehensive identification, fragmentation pattern, and metabolic pathways of gefitinib metabolites via UHPLC-Q-TOF-MS/MS: in vivo study of rat plasma, urine, bile, and faeces
Published in Xenobiotica, 2021
Xun Gao, Yue Zhang, Tiantian Feng, Lei Cao, Wenjing Wu, Kunming Qin
Drug metabolism can be defined as the enzyme-catalysed conversion of a drug into chemically distinct products (metabolites). The main function of drug metabolism is detoxification, which maximises the benefits and minimises the side-effects (Pirmohamed 2008, Zhang and Tang 2018). Currently, the in vitro metabolism of GEF has been extensively investigated. Mckillop et al. have identified 16 metabolites of gefitinib in human liver microsomes in vitro (Mckillop et al. 2004b). Liu et al. have identified 34 GEF metabolites in human and mouse liver microsomes (in vitro) (Liu et al. 2015). Alhoshani et al. have focussed on one cyanide and two methoxylamine-adducts reactive metabolites in the rat heart microsomes (in vitro) (Alhoshani et al. 2020). For the in vivo study, Mckillop et al. have described only 9 metabolites in rat, dog and human (Mckillop et al. 2004a), 7 of them were identical to the metabolites identified in this study. Therefore, the study of metabolites and metabolic pathways of GEF in vivo is vital for rational drug use of GEF. In addition, the study of metabolites can lead candidates during lead optimisation. Compared with the parent compound, there is great potential in developing an active metabolite as a drug in terms of improved pharmacodynamics, pharmacokinetics and safety (Fura 2006).