Absolute Oral Bioavailability of Traxoprodil in Cytochrome P450 2D6 Extensive and Poor Metabolisers

Taylor, Timothy J.; Diringer, Kelly; Russell, Tanya L.; Venkatakrishnan, Karthik; Wilner, Keith D.; Crownover, Penelope; Benincosa, Lisa J.; Gibbs, Megan

doi:10.2165/00003088-200645100-00003

Cited by 5 publications

(4 citation statements)

References 12 publications

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“…Traxoprodil also undergoes hepatic first-pass metabolism by CYP2D6 and absolute oral bioavailability was ∼80% in poor metabolizer subjects. Oral bioavailability appeared to be linear and independent of dose in poor metabolizer subjects, in contrast to extensive metabolizers in which oral bioavailability appeared nonlinear and dose dependent [132].…”

Section: Approximation Of F Hmentioning

confidence: 74%

Bioavailability and Bioequivalence

Amore¹

2012

Encyclopedia of Drug Metabolism and Interactions

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From a pharmacokinetic perspective, bioavailability relates systemic exposure to drug absorption, while helping understand mechanisms underlying drug distribution, transport, and metabolism. Bioavailability studies are also designed to demonstrate bioequivalence of test and reference formulations for both new drug and generic drug products. This chapter provides an overview of the interrelated concepts of bioavailability and bioequivalence and their application to characterize human drug disposition. Additionally, for oral drugs, the determinants of bioavailability leading to malabsorption and presystemic elimination by the gut mucosa and liver are described.

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Section: Approximation Of F Hmentioning

confidence: 74%

Bioavailability and Bioequivalence

Amore¹

2012

Encyclopedia of Drug Metabolism and Interactions

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“…CYP2D6 is known to be prone for phenocopying by drug-drug interactions as well as autophenocopying by reducing its own metabolism (Gardiner and Begg, 2006). Concordantly, metabolism by CYP2D6 was described to be easily inhibited (Sindrup et al, 1992;Taylor et al, 2006). This might point to a saturation of brain CYP2D6 with higher CYP2D6 substrate exposure, potentially affecting local serotonin and dopamine syntheses and could explain the occurrence of drug-associated dizziness with stronger CYP2D6 saturation by substrate exposure and genotype.…”

Section: Discussionmentioning

confidence: 99%

“…Assuming CYP2D6 enzyme activity saturation by the intake of more than two CYP2D6 substrates (Sindrup et al, 1992;Taylor et al, 2006), we calculated a simple CYP2D6 saturation score. Therefore, we defined no CYP2D6 saturation as not taking any CYP2D6 substrate at all, moderate CYP2D6 saturation as taking one or two CYP2D6 substrates, and strong saturation as taking three or more CYP2D6 substrates.…”

Section: Classification Of Drugsmentioning

confidence: 99%

CYP2D6 in the Brain: Potential Impact on Adverse Drug Reactions in the Central Nervous System—Results From the ADRED Study

et al. 2021

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Cytochrome P450 (CYP) 2D6 is a polymorphic enzyme expressed in the central nervous system (CNS), important in drug metabolism and with a potentially constitutive role in CNS function such as vigilance. This study aimed to analyze variability in CYP2D6 activity linked to vigilance-related adverse drug reactions (ADRs) in the CNS. A dataset of N = 2939 ADR cases of the prospective multicenter observational trial in emergency departments (EDs) (ADRED; trial registration: DRKS-ID: DRKS00008979) was analyzed. Dizziness as the most frequent reported CNS ADR symptom (12.7% of patients, n = 372) related to vigilance was chosen as the outcome. The association of dizziness with CYP2D6 activity markers was analyzed. The number of CYP2D6 substrates taken, a CYP2D6 saturation score (no, moderate, and strong saturation), a CYP2D6 saturation/inhibition score (no, weak, moderate, and strong), and composed CYP2D6 activity using a genotyped subsample (n = 740) calculating additive effects of genotype and CYP2D6 saturation by drug exposure were used as CYP2D6 activity markers. Effects were compared to other frequent nonvigilance-related CNS ADR symptoms (syncope and headache). Secondary analyses were conducted to control for other ADR symptoms frequently associated with dizziness (syncope, nausea, and falls). The majority of all patients (64.5%, n = 1895) took at least one drug metabolized by CYP2D6. Around a third took a CNS drug (32.5%, n = 955). The chance to present with drug-related dizziness to the ED increased with each CYP2D6 substrate taken by OR 1.11 [1.01–1.23]. Presenting with drug-related dizziness was more likely with CYP2D6 saturation and saturation/inhibition (both OR 1.27 [1.00–1.60]). The composed CYP2D6 activity was positively associated with dizziness (p = 0.028), while poorer activity affected patients more often with dizziness as an ADR. In contrast, nonvigilance-related ADR symptoms such as syncope and nausea were not consistently significantly associated with CYP2D6 activity markers. This study shows an association between the number of CYP2D6 substrates, the predicted CYP2D6 activity, and the occurrence of dizziness as a CNS ADR symptom. As dizziness is a vigilance-related CNS symptom, patients with low CYP2D6 activity might be more vulnerable to drug-related dizziness. This study underlines the need for understanding individual drug metabolism activity and individual risks for ADRs.

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“…The nonlinear kinetics of extensive metabolizers is probably due to the saturation of the CYP2D6 enzyme itself. Unlike the in vivo LTP study where normal SD rats were used, a possible genetic polymorphism, regarding the metabolism of animal models of CNS disorders, should be investigated to correctly interpret the corresponding LTP results [76,77].…”

Section: Cp-101606 Andmentioning

confidence: 99%

NMDARs Containing NR2B Subunit Do Not Contribute to the LTP Form of Hippocampal Plasticity: In Vivo Pharmacological Evidence in Rats

Ahnaou

Heleven

Biermans

et al. 2021

IJMS

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Synaptic plasticity is the key to synaptic health, and aberrant synaptic plasticity, which in turn impairs the functioning of large-scale brain networks, has been associated with neurodegenerative and psychiatric disorders. The best known and most studied form of activity-dependent synaptic plasticity remains long-term potentiation (LTP), which is controlled by glutamatergic N-methyl-d-aspartate) receptors (NMDAR) and considered to be a mechanism crucial for cellular learning and memory. Over the past two decades, discrepancies have arisen in the literature regarding the contribution of NMDAR subunit assemblies in the direction of NMDAR-dependent synaptic plasticity. Here, the nonspecific NMDAR antagonist ketamine (5 and 10 mg/kg), and the selective NR2B antagonists CP-101606 and Ro 25-6981 (6 and 10 mg/kg), were administered intraperitoneally in Sprague Dawley rats to disentangle the contribution of NR2B subunit in the LTP induced at the Schaffer Collateral-CA1 synapse using the theta burst stimulation protocol (TBS). Ketamine reduced, while CP-101606 and Ro 25-6981 did not alter the LTP response. The administration of CP-101606 before TBS did not influence the effects of ketamine when administered half an hour after tetanization, suggesting a limited contribution of the NR2B subunit in the action of ketamine. This work confirms the role of NMDAR in the LTP form of synaptic plasticity, whereas specific blockade of the NR2B subunit was not sufficient to modify hippocampal LTP. Pharmacokinetics at the doses used may have contributed to the lack of effects with specific antagonists. The findings refute the role of the NR2B subunit in the plasticity mechanism of ketamine in the model.

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Absolute Oral Bioavailability of Traxoprodil in Cytochrome P450 2D6 Extensive and Poor Metabolisers

Cited by 5 publications

References 12 publications

Bioavailability and Bioequivalence

Bioavailability and Bioequivalence

CYP2D6 in the Brain: Potential Impact on Adverse Drug Reactions in the Central Nervous System—Results From the ADRED Study

NMDARs Containing NR2B Subunit Do Not Contribute to the LTP Form of Hippocampal Plasticity: In Vivo Pharmacological Evidence in Rats

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