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Pharmacokinetic determinants of clinical activity
Published in Adam Doble, Ian L Martin, David Nutt, Calming the Brain: Benzodiazepines and related drugs from laboratory to clinic, 2020
Adam Doble, Ian L Martin, David Nutt
The vast majority of benzodiazepines are metabolised in the liver by Type I oxidation involving cytochrome P450 enzymes (Chouinard et al, 1999). N1-Dealkylation is a particularly common route of metabolism, occurring for the vast majority of benzodiazepines substituted in this position. For the triazolobenzodiazepines, in which this route is not available, the principal metabolic pathway is α-hydroxylation of the triazolo ring by CYP3A subtypes, followed by scission of the benzodiazepine ring, as well as by 4-hydroxylation (Gorski et al, 1994, 1999; Perloff et al, 2000). Zopiclone is transformed into three metabolites (by demethylation, decarboxylation and N-oxidation) by CYP2C8 and CYP3A4 (Becquemont et al, 1999), as is zolpidem (by demethylation at the 5- and 4′-positions, and by ring hydroxylation), principally by CYP3A4 (Pichard et al, 1995). Zaleplon has a single major metabolite, 5-oxozaleplon, formed by aldehyde oxidase (Lake et al, 2002).
The Metabolism of Amphetamines and Related Stimulants in Animals and Man
Published in John Caldwell, S. Joseph Mulé, Amphetamines and Related Stimulants: Chemical, Biological, Clinical, and Sociological Aspects, 2019
N-dealkylation alone is a reaction of significance, since it commonly gives rise to primary amine products which retain pharmacological activity, e.g., amphetamine from a range of N-alkylated amphetamines and norephedrine from ephedrine.
Clinical Pharmacogenomics Of Human Cyp2d6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Opioids have long been used as potent analgesics. They bind to specific opioid receptors (µ, κ, and δ) in the CNS and in other tissues and produce different pharmacological response depending on which receptor they bind, the affinity for that receptor, and whether the opioid is an agonist or an antagonist. Almost all opioids are subject to O-dealkylation, N-dealkylation, ketoreduction, or deacetylation leading to oxi-dative metabolites (Lotsch 2005). Through glucuronidation or sulfation, Phase II metabolites are generated. Some metabolites of opioids have an activity themselves and contribute to the effects of the parent compound. CYP2D6 is involved in the oxidative metabolism of several opioids, including dex-tromethorphan, tramadol, codeine, dihydrocodeine, hydroco-done, and oxycodone (Leppert 2011).
Employing in vitro metabolism to guide design of F-labelled PET probes of novel α-synuclein binding bifunctional compounds
Published in Xenobiotica, 2021
Chukwunonso K. Nwabufo, Omozojie P. Aigbogun, Kevin J.H Allen, Madeline N. Owens, Jeremy S. Lee, Christopher P. Phenix, Ed S. Krol
1-Aminoindan is a P450 metabolite of the Parkinson’s disease therapeutic rasagiline and, 1-aminoindan can be further metabolized to 3-hydroxy-1-aminoindan (Deftereos et al. 2012; Agundez et al. 2013; de Biase et al. 2014). We identified a hydroxylated metabolite of C8-6-I and tandem mass spectrometric analysis suggests that the hydroxyl group is located on the 1-aminoindan moiety, what is less clear is the position of hydroxylation on the 1-aminoindan moiety. We have proposed reactions for the dealkylation and hydroxylation of C8-6-I (Figure 4(A)). Dealkylation requires initial hydroxylation to occur at the 1-position followed by breakdown of the carbinolamine to form M1 with the concomitant loss of 1-oxoindan (Figure 4(A)). Hydroxylation of C8-6-I is more likely to occur at the benzylic 3-position to give M2. It has been suggested that 3-hydroxy-1-aminoindan may have neuroprotective effects (Sterling et al. 1998), therefore M2 may also be neuroprotective. Additionally, given that M1 still contains the caffeine moiety, it may also possess neuroprotective properties.
Identification of novel glutathione conjugates of terbinafine in liver microsomes and hepatocytes across species
Published in Xenobiotica, 2019
Amol Patil, Mayurbhai Kathadbhai Ladumor, Shyam H Kamble, Benjamin M. Johnson, Murali Subramanian, Michael W. Sinz, Dilip Kumar Singh, Sivaprasad Putlur, Priyadeep Bhutani, Deepak Suresh Ahire, Saranjit Singh
The third category includes metabolites formed by N-dealkylation, resulting in liberation of the conjugated side chain followed by reaction of the side chain with GSH. This category includes conjugates of the allylic aldehyde, which is the immediate product of N-dealkylation, as well as downstream products of redox reactions that convert the aldehyde to either alcohol or acid metabolites. The aldehyde (M11 and M17) and acid intermediates (M8 and M20) represent potential Michael acceptors that could undergo direct nucleophilic attack by the sulfhydryl residue of GSH via 1,4- or 1,6-addition. Interestingly, we have also identified metabolites formed by GSH conjugation to the allylic alcohol, which is not a Michael acceptor. The mechanism of the GSH conjugate formation to the allylic alcohol has not been defined. One could hypothesize about involvement of a GSH S-transferase in facilitating the reaction with the alcohol as a substrate, or about action of aldehyde dehydrogenase in reducing the aldehyde subsequent to GSH conjugate formation. It should be noted that the GSH conjugates of the allyl alcohol and allyl acids were of much lower abundance in these systems relative to the allyl aldehyde analog, reflecting the expected trend based on chemical reactivity.
Efficacy and safety of cariprazine in the treatment of bipolar disorder
Published in Expert Opinion on Pharmacotherapy, 2019
Gayatri Saraf, Jairo Vinícius Pinto, Lakshmi N. Yatham
Cariprazine is rapidly absorbed, reaching peak concentrations within 3–4 hours of an oral dose. The absorption is marginally decreased by food [50,51]. Once absorbed, cariprazine is extensively distributed in tissues, with a large volume of distribution. It is primarily metabolized by the liver, where it undergoes dealkylation, hydroxylation, N-oxidation, and cleavage. Cariprazine is extensively broken down by CYP3A4, and to a lesser extent by CYP2D6 into desmethyl-cariprazine and didesmethyl-cariprazine. Desmethyl-cariprazine is further broken down to didesmethyl-cariprazine, which then undergoes hydroxylation into other metabolites [37]. For this reason, the dose of cariprazine should be halved in the presence of a concurrent CYP3A4 inhibitor. Potent CYP3A4 inducers, such as carbamazepine, or potent CYP3A4 inhibitors, such as ketoconazole, may influence the plasma levels of cariprazine [52]. This should be specially noted before prescribing cariprazine to patients who are on carbamazepine as a mood stabilizer. Valproate also inhibits CYP3A4, although to a lesser extent than other CYP enzymes, so potential drug interactions need to be kept in mind for patients who are on a concurrent mood stabilizer [53].