Influence of CYP2D6 genetic polymorphism on pharmacokinetics of active moiety of tolterodine

Byeon, J.Y.; Lee, Choong-Min; Lee, Yea-Jin; Kim, Young-Hoon; Kim, Se-Hyung; Jung, Eui Hyun; Chae, Won Ki; Lee, Yun Jeong; Jang, Choon‐Gon; Lee, Seok‐Yong

doi:10.1007/s12272-018-1099-y

Cited by 22 publications

(5 citation statements)

References 42 publications

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“…The single dose and multiple dose C Max and AUC 0–24 of tolterodine, respectively, were significantly higher in the PM groups than in the EMs. The ratio of clearance to bioavailability of tolterodine in the EMs was 5‐ to 18‐fold higher than PM (variant dependent) in multiple dosing studies 147 . A Swedish study also found a difference in the absorption t 1/2 of tolterodine between EM (0.41 h) and PM (0.53 h), and EM were found to have a slight increase in heart rate at steady state in comparison with baseline, which was thought to be related to drug exposure 148 .…”

Section: Resultsmentioning

confidence: 90%

“…The ratio of clearance to bioavailability of tolterodine in the EMs was 5-to 18-fold higher than PM (variant dependent) in multiple dosing studies. 147 A Swedish study also found a difference in the absorption t 1/2 of tolterodine between EM (0.41 h) and PM (0.53 h), and EM were found to have a slight increase in heart rate at steady state in comparison with baseline, which was thought to be related to drug exposure. 148 Interest in understanding druginduced QT interval prolongation led to study of the effect of CYP2D6 polymorphism on ECG changes in the use of tolterodine and its active metabolite 5-HMT.…”

Section: Geneticsmentioning

confidence: 94%

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

Trenaman

Bowles

Andrew

et al. 2021

Pharmacology Res & Perspec

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Section: Resultsmentioning

confidence: 90%

Section: Geneticsmentioning

confidence: 94%

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

Trenaman

Bowles

Andrew

et al. 2021

Pharmacology Res & Perspec

View full text Add to dashboard Cite

show abstract

“…The single dose and multiple dose C Max and AUC 0-24 of tolterodine was significantly higher in the PM groups than in the EMs. The ratio of clearance to bioavailability of tolterodine in the EMs was 5 to 18-fold higher than PM (variant dependent) in multiple dosing studies 126 . A Swedish study also found a difference in the absorption t 1/2 of tolterodine between EM (0.41 h) and PM (0.53 h) and EM were found to have a slight increase in heart rate at steady state in comparison to baseline which was thought to be related to drug exposure 127 .…”

Section: Cyp2d6mentioning

confidence: 85%

The Role of Sex, Age and Genetic Polymorphisms of CYP Enzymes on the Pharmacokinetics of Anticholinergic Drugs

Trenaman

Bowles

Andrew

et al. 2020

Preprint

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Drugs exhibiting anticholinergic properties are commonly used by older adults even with the associated risk of adverse drug events. Aging, sex and genetic polymorphisms of cytochrome P450 (CYP) enzymes are associated with alterations in pharmacokinetic processes which may increase drug exposure and further increase the risk of adverse drug events. Age-related changes include; pseudocapillarization of liver sinusoidal endothelial cells which limit passage of drugs through the liver, an approximate 3.5% decline in CYP450 content for each decade of life, and a reduction in kidney function reducing drug excretion. Sex-related differences include; women having delayed gastric and colonic emptying, higher gastric pH, reduced catechol-O-methyl transferase activity, reduced glucuronidation, and reduced renal clearance and men having larger stomachs which may allow them to dissolve and absorb medication more completely. The overlay of poor metabolism phenotypes for CYP2D6 and CYP2C19 may further modify anticholinergic drug exposure in a significant proportion of the population. These factors help explain clinical trials that show older adults and specifically women achieve higher plasma concentrations of anticholinergic drugs. Despite this knowledge, age and sex are rarely considered when making decisions about the dosing of anticholinergic medications. As this is relevant to the future use of personalized medicine, the objective of this review is to provide a clinical perspective on age, sex, and CYP genetic polymorphisms and their role in the metabolism and exposure to anticholinergic drugs. Future work needs to account for age, sex and CYP polymorphism so that we may better approach personalized medicine for optimal outcomes.

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“…The metabolic oxidation also included hydroxylation of the unsubstituted phenyl rings. The metabolism of TOL produced 3–5 metabolites in mouse, rat, dog, and human liver microsomal incubations. , These incubations offered 5-hydroxymethyl TOL and N -dealkylated TOL as major oxidative metabolites, accounting for 83–99% of the total metabolism. , CYP2D6 was found to be responsible for the production of 5-hydroxymethyl TOL, and CYP3A4 dominated the metabolic N -dealkylation of TOL. − …”

Section: Introductionmentioning

confidence: 96%

“…In these species, TOL undergoes two distinct metabolic pathways, the more important of which is the progressive oxidation of the 5-methyl group to produce the 5-hydroxymethyl metabolite of TOL, followed by further oxidation to the corresponding aldehyde and then to the 5-carboxylic acid metabolite. Another pathway involved the dealkylation of nitrogen. − Extensive biotransformation of TOL, along with various types of metabolites generated, was found in rats. The metabolic oxidation also included hydroxylation of the unsubstituted phenyl rings.…”

Section: Introductionmentioning

confidence: 99%

In Vitro and In Vivo Metabolic Activation of Tolterodine Mediated by CYP3A

Wang

Zhao

Liu

et al. 2023

Chem. Res. Toxicol.

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Tolterodine (TOL) is an antimuscarinic drug used for the treatment of patients with overactive bladder presenting urinary frequency, urgency, and urge incontinence. During the clinical use of TOL, adverse events such as liver injury took place. The present study aimed at the investigation of the metabolic activation of TOL possibly associated with its hepatotoxicity. One GSH conjugate, two NAC conjugates, and two cysteine conjugates were found in both mouse and human liver microsomal incubations supplemented with TOL, GSH/NAC/cysteine, and NADPH. The detected conjugates suggest the production of a quinone methide intermediate. The same GSH conjugate was also observed in mouse primary hepatocytes and in the bile of rats receiving TOL. One of the urinary NAC conjugates was observed in rats administered TOL. One of the cysteine conjugates was found in a digestion mixture containing hepatic proteins from animals administered TOL. The observed protein modification was dose-dependent. CYP3A primarily catalyzes the metabolic activation of TOL. Ketoconazole (KTC) pretreatment reduced the generation of the GSH conjugate in mouse liver and cultured primary hepatocytes after TOL treatment. In addition, KTC reduced the susceptibility of primary hepatocytes to TOL cytotoxicity. The quinone methide metabolite may be involved in TOL-induced hepatotoxicity and cytotoxicity.

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Influence of CYP2D6 genetic polymorphism on pharmacokinetics of active moiety of tolterodine

Cited by 22 publications

References 42 publications

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

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

The Role of Sex, Age and Genetic Polymorphisms of CYP Enzymes on the Pharmacokinetics of Anticholinergic Drugs

In Vitro and In Vivo Metabolic Activation of Tolterodine Mediated by CYP3A

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