Overview of the Biotransformation of Antiepileptic Drugs
Carl L. Faingold, Gerhard H. Fromm in Drugs for Control of Epilepsy:, 2019
This brief overview of the biotransformation of anticonvulsant drugs, portions of which are summarized in Table 1, calls attention to several facts. First, several of the older drugs have a structural common denominator, a point emphasized in past discussions of structure-activity relationships.62 Thus, it is not surprising that many drugs have similar pathways of biotransformation. Second, several important antiepileptic drugs are transformed into metabolites that have anticonvulsant effects. Therefore, any discussion of mechanisms of action or toxicities must consider the contributions of the active metabolite(s) as well as the parent drug. Third, the fact that reactive metabolites play a major role in the toxicity of several drugs is quite clear. It is likely that this area of research will receive considerable attention. Fourth, the importance of polymorphism and chirality of anticonvulsant drug biotransformation has not been adequately studied and much remains to be done. Finally, as Levy and Kerr63 have so clearly pointed out, detailed knowledge of anticonvulsant drug biotransformations will aid in the future design of antiepileptic drugs with less toxicity and more effectiveness.
Safety Pharmacology and the GI Tract
Shayne C. Gad in Toxicology of the Gastrointestinal Tract, 2018
Generally, any parent compound and its major metabolites that achieve, or are expected to achieve, systemic exposure in humans should be evaluated in safety pharmacology studies. Evaluation of major metabolites is often accomplished through studies of the parent compound in animals. If the major human metabolites are found to be absent or present only at relatively low concentrations in animals, assessment of the effects of such metabolites on safety pharmacology endpoints should be considered. If metabolites from humans are known to substantially contribute to the pharmacological actions of the therapeutic agent, it could be important to test such active metabolites. When the in vivo studies on the parent compound have not adequately assessed metabolites, the tests of metabolites can be used in in vitro systems based on practical considerations. In vitro or in vivo testing of the individual isomers should also be considered when the product contains an isomeric mixture.
Antidepressants: Predicting Response/Maximizing Efficacy
Mark S. Gold, R. Bruce Lydiard, John S. Carman in Advances in Psychopharmacology: Predicting and Improving Treatment Response, 2018
For other tricyclics, other antidepressants, and most anticonvulsants, therapeutic levels are best described as thresholds required for therapeutic efficacy.7,8 For antidepressants that are metabolized to substances that are themselves antidepressant, these “active metabolites” must be taken into account also. Thus, amitriptyline is metabolized to nortriptyline, and imipramine is metabolized to desipramine. For patients taking either of the parent medications, plasma levels of both parent and active metabolite must be measured. Therapeutic, steady-state plasma levels for patients on amitriptyline are amitriptyline plus nortriptyline greater than 120 ng/mℓ; for patients on imipramine are impramine plus desipramine greater than 180 ng/mℓ; and for desipramine a therapeutic window may exist but this remains unclear at present. There are preliminary data on therapeutic levels of other antidepressants as well. Table 5 summarizes the usual dosage ranges and therapeutic concentrations which we currently suggest as guidelines for treatment. Measurement of platelet MAO activity can guide proper dosage of MAOI. There are a number of reports that optimal phenelzine response requires at least 80% inhibition of platelet MAO from pretreatment baselines.41
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).
Deutetrabenazine for the treatment of Huntington’s chorea
Published in Expert Review of Neurotherapeutics, 2018
Hassaan Bashir, Joseph Jankovic
Human PET-scan studies have shown that following intravenous 11C-labeled TBZ or alpha-HTBZ, they are rapidly distributed to the brain and show highest binding in the striatum and lowest in the cortex [28]. Deutetrabenazine has a half-life of approximately 9–10 hours allowing twice a day dosing, compared to a half-life of 5–7 hours for TBZ [31]. Both, parent drug and active metabolites are eliminated via kidneys [28,30]. No clinical studies have yet been done to evaluate the pharmacokinetics of deutetrabenazine in patients with renal or hepatic impairment. Data for hepatic impairment is extrapolated from studies of TBZ which showed that the exposure to active metabolites was 40% greater and that the mean TBZ Cmax was up to 190-fold higher than in healthy subjects [28]. Furthermore, there are no specific studies looking at poor CYP2D6 metabolizers where it can be expected that exposure to alpha and beta-HTBZ will be also increased, similar to taking a strong CYP2D6 inhibitor (Mehanna et al., 2013).
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.
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