Measurement of oxybutynin and its N-desethyl metabolite in plasma, and its application to pharmacokinetic studies in young, elderly and frail elderly volunteers

Abstract

1. A quantitative h.p.l.c. plasma assay for oxybutynin (OB) and its active metabolite, N-desethyl oxybutynin (DEOB) is described. The method is linear with coefficients of variation ranging between 4 and 11.8% for OB and 4.6-9.1% for DEOB over the typical concentration range measured. Minimum detectable levels were 0.5 and 5 ng/ml for OB and DEOB respectively from a 2 ml sample. 2. Pharmacokinetic parameters were obtained after a single oral dose of OB and after administration two or three times daily to frail elderly and elderly volunteer groups respectively. Single dose results were also compared with data from young healthy volunteers. 3. There was a wide range in peak blood levels and high levels of parent drug were matched by high DEOB metabolite levels. Plasma levels on repeated administration were as would be predicted from the single dose kinetics. 4. Area under the plasma time course curve for DEOB metabolite was less than or equal to 5 than that of the parent drug. 5. A trend of increasing peak plasma levels and bioavailability was observed with increasing age and frailty, with the differences more apparent between the active elderly and frail elderly groups than between the active elderly and young volunteers. 6. Results indicate that for frail elderly patients a lower initial starting dose of 2.5 mg OB given two or three times a day may provide adequate therapeutic blood levels of the drug.

Effects of 4-Ethylamino-2-butynyl(2-cyclohexyl-2-phenyl)glycolate Hydrochloride, a Metabolite of Oxybutynin, on Bladder Specimens and Rhythmic Bladder Contraction in Rats in Comparison With Oxybutynin

“…In the human pharmacokinetic volunteer study, we found that the serum level of DEOB was higher than that of oxybutynin in case of oral administration (data not shown). Hughes et al (32) reported that high levels of orally administered oxybutynin were matched by high DEOB metabolite levels in young, elderly and frail elderly volunteers. Moreover, Saitoh et al (33) also reported that plasma levels of oxybutynin were almost equal to those of DEOB even in the instillation of intravesical oxybutynin in overactive bladder patients.…”

Anticholinergiques et hyperactivité vésicale

“…C'est une amine tertiaire qui a pour métabolite actif la N-déséthyloxybutynine [25][26][27] . Stohrer a signalé une amélioration de la capacité vésicale de 164 ml à 298 ml, avec diminution de la pression détrusorienne maximale de 68,6 cm H 2 O à 43 cm H 2 O chez des patients présentant une hyperactivité détrusorienne 28 .…”

“…Stohrer a signalé une amélioration de la capacité vésicale de 164 ml à 298 ml, avec diminution de la pression détrusorienne maximale de 68,6 cm H 2 O à 43 cm H 2 O chez des patients présentant une hyperactivité détrusorienne 28 . D'autres formules d'oxybutynine permettent de limiter les effets secondaires ; c'est notamment le cas de la formule à libération prolongée (prise quotidienne), du timbre cutané, du gel topique, du suppositoire et du médicament en instillation intravésicale [25][26][27] . L'essai aléatoire à double insu OPERA a permis d'étudier, pendant 12 semaines, l'efficacité de l'oxybutynine à libération prolongée (10 mg) auprès de 790 femmes.…”

The Forefront for Novel Therapeutic Agents Based on the Pathophysiology of Lower Urinary Tract Dysfunction: Bladder Selectivity Based on In Vivo Drug–Receptor Binding Characteristics of Antimuscarinic Agents for Treatment of Overactive Bladder

“…It is known that orally administered oxybutynin is rapidly absorbed from the gastrointestinal tract with the major pathway of elimination by hepatic metabolism (28) and that the plasma concentration of DEOB in humans after oral administration is much higher than that of oxybutynin (29). Based on previous reports that muscarinic receptor binding affinity of DEOB was greater in the salivary gland than in the bladder (30,31), it is considered that DEOB may be responsible for the longlasting occupation of exocrine muscarinic receptors after oral oxybutynin.…”