The role of sex, age and genetic polymorphisms of CYP enzymes on the pharmacokinetics of anticholinergic drugs

Trenaman, Shanna C; Bowles, Susan K.; Andrew, Melissa K.; Goralski, Kerry B.

doi:10.1002/prp2.775

Cited by 21 publications

(15 citation statements)

References 144 publications

(313 reference statements)

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“…Regulation of P450 eicosanoid levels is determined by the induction or repression of the cytochrome P450 enzymes responsible for their formation ( Ng et al, 2007 ). According to a previous study, an approximate 3.5% decline in CYP450 content occurs for each decade of life ( Trenaman et al, 2021 ). Therefore, a higher 14,15-DiHETrE level in youth age probably results from higher CYP 450 content at the young.…”

Section: Discussionmentioning

confidence: 93%

Characterization of LC-MS based urine metabolomics in healthy children and adults

Liu

Tian

Shi

et al. 2022

PeerJ

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Previous studies reported that sex and age could influence urine metabolomics, which should be considered in biomarker discovery. As a consequence, for the baseline of urine metabolomics characteristics, it becomes critical to avoid confounding effects in clinical cohort studies. In this study, we provided a comprehensive lifespan characterization of urine metabolomics in a cohort of 348 healthy children and 315 adults, aged 1 to 78 years, using liquid chromatography coupled with high resolution mass spectrometry. Our results suggest that sex-dependent urine metabolites are much greater in adults than in children. The pantothenate and CoA biosynthesis and alanine metabolism pathways were enriched in early life. Androgen and estrogen metabolism showed high activity during adolescence and youth stages. Pyrimidine metabolism was enriched in the geriatric stage. Based on the above analysis, metabolomic characteristics of each age stage were provided. This work could help us understand the baseline of urine metabolism characteristics and contribute to further studies of clinical disease biomarker discovery.

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Section: Discussionmentioning

confidence: 93%

Characterization of LC-MS based urine metabolomics in healthy children and adults

Liu

Tian

Shi

et al. 2022

PeerJ

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“…This may be along with the increase of age, the physiological function and compensatory adaptability of the human body are decreased year by year, and the effects of the body on the clearance rate of liver and kidney drugs are also decreased. Besides, CYP450 changes with age (Trenaman et al ., 2021). However, there is no difference in RIS/9-OH-RIS among people of different ages.…”

Section: Discussionmentioning

confidence: 99%

Relationship between clinical efficacy and plasma concentration-dose ratio of risperidone in patients with schizophrenia

Chen¹,

Min

Yin³

et al. 2023

International Clinical Psychopharmacology

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This study aimed to retrospectively explore the relationship between clinical efficacy and plasma concentration–dose ratio of risperidone (RIS) in 252 patients with schizophrenia taking RIS orally. After the same dose of RIS treatment, the plasma concentration of RIS/9-hydroxyrisperidone (9-OH-RIS), the total plasma concentration of RIS, and the ratio of the steady-state plasma concentration to the daily dose of the total active product (C/D) showed individual difference. The RIS plasma concentration was significantly higher in patients taking high doses than those taking lower doses (P = 0.003). There was a statistically significant difference in C/D ratio between males and females (P = 0.003). There were significant differences in ratio of C/D and the total plasma concentration of RIS between patients under 60 years and over 60 years (P = 0.016; P = 0.005). Logistic regression analysis showed that the therapeutic effect and adverse reactions of RIS were correlated with the ratio of C/D in patients with schizophrenia (P = 0.038; P < 0.001). It has been suggested that the importance of monitoring of the plasma concentration of RIS in patients with schizophrenia and the ratio of C/D may be used as the reference for RIS personalized treatment.

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“…The rapid antidepressant effect of scopolamine was observed in both sexes; however, one study showed the magnitude was higher in women than men, which may be driven by renal elimination rate. Although there are no studies examining pharmacokinetic differences of scopolamine in men versus women, results from drugs with weak anticholinergic activity such as amantadine and digoxin suggest slower clearance in females compared to males, due to sex differences in renal tubule secretion by organic cation transporters [ 106 ]. A second possibility is p-glycoprotein transporter polymorphisms may lead to variability in efficacy [ 76 , 107 ].…”

Section: Discussionmentioning

confidence: 99%

Clinical Effectiveness of Muscarinic Receptor-Targeted Interventions in Neuropsychiatric Disorders: A Systematic Review

2022

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Background For decades, treatment of mood disorders, psychoses, anxiety and dementia have been confounded by limited efficacy and high rates of treatment resistance. Preclinical and clinical evidence have highlighted disruption of cholinergic signalling in several neuropsychiatric conditions and examined intervention strategies including acetylcholinesterase inhibitors and nicotinic receptor-targeted intervention. However, the effectiveness of these approaches is often curtailed by ontarget side effects. Post mortem studies implicate muscarinic receptor dysregulation in neuropsychiatric pathophysiology; therefore, we conducted a systematic review and meta-analysis to investigate the therapeutic efficacy and safety of muscarinic receptor-targeted interventions in adults with neuropsychiatric disorders. Methods PubMed, EMBASE, PsycINFO, EBSCO and Web of Science were searched using relevant keywords from database inception to 7 August 2022. Randomised, double-blind, placebo-controlled studies were included if they investigated the effect of muscarinic receptor-targeted intervention in adults with a diagnosis of a neuropsychiatric disorder and were published in English. A narrative synthesis approach was adopted to describe the findings. Wherever three or more studies with a similar intervention were available, effect sizes were calculated, and a meta-analysis was performed. Cochrane riskof-bias-2 tool was utilised to assess the risk of bias, and sensitivity analyses were performed to identify publication bias. Certainty analysis (high, moderate, low and/or very low) was conducted using GRADE criteria. Results Overall, 33 studies met the inclusion criteria and 5 were included in the meta-analysis. Despite a limited pool with several different interventions, we found therapeutic efficacy of xanomeline (M 1 /M 4 agonist) in primary psychotic disorders plus behavioural and psychological symptoms of dementia. Scopolamine showed a significant antidepressant effect in a combined cohort of major depressive and bipolar disorders in the short-term outcome measure, but no effect following cessation of treatment. Results from bias assessments suggest "very low" certainty in the antidepressant effect of scopolamine. Critical limitations of the current literature included low power, high heterogeneity in the patient population and a lack of active comparators. Conclusion While the results are not definitive, findings on muscarinic receptor-targeted interventions in several mental disorders are promising in terms of efficacy and safety, specifically in treating schizophrenia, mood disorders, and behavioural and psychiatric symptoms of Alzheimer's disease. However, orthosteric muscarinic receptor-targeted interventions are associated with a range of peripheral adverse effects that are thought to be mediated via M 2 /M 3 receptors. The orthosteric binding site of muscarinic acetylcholine receptors is remarkably conserved, posing a challenge for subtype-selective interventions; nonetheless allosteric ligands with biased signalling pa...

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The role of sex, age and genetic polymorphisms of CYP enzymes on the pharmacokinetics of anticholinergic drugs

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 21 publications

References 144 publications

Characterization of LC-MS based urine metabolomics in healthy children and adults

Characterization of LC-MS based urine metabolomics in healthy children and adults

Relationship between clinical efficacy and plasma concentration-dose ratio of risperidone in patients with schizophrenia

Clinical Effectiveness of Muscarinic Receptor-Targeted Interventions in Neuropsychiatric Disorders: A Systematic Review

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