Chemical formula: C₂₂H₃₁NO₃ Molecular mass: 357.486 g/mol PubChem compound: 4634
Oxybutynin acts as a competitive antagonist of acetylcholine at post-ganglionic muscarinic receptors, resulting in relaxation of bladder smooth muscle.
In patients with overactive bladder, characterised by detrusor muscle instability or hyperreflexia, cystometric studies have demonstrated that oxybutynin increases maximum urinary bladder capacity and increases the volume to first detrusor contraction. Oxybutynin thus decreases urinary urgency and the frequency of both incontinence episodes and voluntary urination.
Oxybutynin is a racemic (50:50) mixture of R- and S-isomers. Antimuscarinic activity resides predominantly in the R-isomer. The R-isomer of oxybutynin shows greater selectivity for the M1 and M3 muscarinic subtypes (predominant in bladder detrusor muscle and parotid gland) compared to the M2 subtype (predominant in cardiac tissue). The active metabolite, N-desethyloxybutynin, has pharmacological activity on the human detrusor muscle that is similar to that of oxybutynin in vitro studies, but has a greater binding affinity for parotid tissue than oxybutynin. The free base form of oxybutynin is pharmacologically equivalent to oxybutynin hydrochloride.
Following the first dose of oxybutynin prolonged release tablet, oxybutynin plasma concentrations rise for 4 to 6 hours; thereafter, concentrations are maintained for up to 24 hours, thus reducing the fluctuations between peak and trough concentrations associated with oxybutynin immediate release formulations. Absolute bioavailability of immediate release oxybutynin has been estimated to be 2-11%. The relative bioavailabilities of R-oxybutynin and S-oxybutynin from oxybutynin prolonged release tablet are 156% and 187% respectively, compared with oxybutynin immediate release. After a 10 mg single dose, the peak plasma concentrations of R-oxybutynin and S-oxybutynin, achieved after 12.7±5.4 and 11.8±5.3 hours respectively, are 1.0±0.6 and 1.8±1.0 ng/ml, and the plasma concentration time profiles of both enantiomers are similar in shape.
The pharmacokinetics of oxybutynin prolonged release tablet are unaffected by food intake.
Oxybutynin has a concentration of oxybutynin sufficient to maintain continuous transport over the 3 to 4 day dosing interval. Oxybutynin is transported across intact skin and into the systemic circulation by passive diffusion across the stratum corneum. Following the application, oxybutynin plasma concentration increases for approximately 24 to 48 hours, reaching average maximum concentrations of 3 to 4 ng/ml. Steady-state conditions are reached during the second application of the transdermal patch. Thereafter, steady concentrations are maintained for up to 96 hours. The difference in AUC and Cmax of oxybutynin and the active metabolite N-desethyloxybutynin following transdermal administration of oxybutynin on either the abdomen, buttocks or hip is not clinically relevant.
Oxybutynin is widely distributed in body tissues following systemic absorption. The volume of distribution was estimated to be 193 L after intravenous administration of 5 mg oxybutynin hydrochloride. Both enantiomers of oxybutynin are highly bound (>99%) to plasma proteins. Both enantiomers of desethyloxybutynin are also highly bound (>97%) to plasma proteins. The major binding protein is alpha-1 acid glycoprotein.
Oxybutynin is extensively metabolised by the liver, primarily by the cytochrome P450 enzyme system, particularly CYP3A4 found mostly in the liver and gut wall. Its metabolic products include phenylcyclohexylglycolic acid, which is pharmacologically inactive, and desethyloxybutynin, which is pharmacologically active.
Following oral administration, area under the plasma concentration profiles of R- and S-desethyloxybutynin are 73% and 92%, respectively of those observed with oxybutynin immediate release formulations. Following intravenous administration of 5 mg oxybutynin, clearance was estimated to be 26 L/h. Less than 0.1% of the administered dose is excreted unchanged in the urine. The elimination half-life is 13.2±10.3 hours for R-oxybutynin and 12.4±6.1 hours for S-oxybutynin.
Transdermal administration of oxybutynin bypasses the first-pass gastrointestinal and hepatic metabolism, reducing the formation of the N-desethyl metabolite.
Oxybutynin is extensively metabolised by the liver, see above with less than 0.1% of the administered dose excreted unchanged in the urine. Also, less than 0.1% of the administered dose is excreted as the metabolite N-desethyloxybutynin.
The steady-state pharmacokinetics of oxybutynin prolonged release tablet were evaluated in a limited number of children aged 6-15 years with detrusor overactivity associated with a neurological condition (e.g. spina bifida) receiving 10 or 15 mg total daily doses of oxybutynin. The pharmacokinetics of oxybutynin in these paediatric patients were consistent with those reported for adults. The table below summarizes maximum and average plasma concentrations for each of the four analytes, R- and S-Oxybutynin and R- and S-Desethyloxybutynin, by age group and total daily dose.
Mean (SD) Maximum and Average Concentrations (ng/mL) of R- and S-Oxybutynin and R- and S-Desethyloxybutynin in Children Following Administration of 10 and 15 mg oxybutynin prolonged release tablet Once Daily:
| Age <10 yrsa | Age >10 yrsb | |||
|---|---|---|---|---|
| Dose/Analyte | Cmax | Cavg | Cmax | Cavg |
| 10 mg Dose | ||||
| R-Oxybutynin | 1.39 (0.1) | 0.91 (0.2) | 1.37 (0.9) | 1.06 (0.8) |
| S-Oxybutynin | 2.46 (0.5) | 1.58 (0.5) | 2.45 (1.7) | 2.00 (1.5) |
| R-Desethyloxybutynin | 15.4 (2.2) | 8.74 (2.8) | 13.2 (9.7) | 9.48 (6.8) |
| S-Desethyloxybutynin | 6.81 (0.9) | 4.38 (1.8) | 8.05 (6.7) | 6.70 (6.1) |
| 15 mg Dose | ||||
| R-Oxybutynin | 2.59 (1.4) | 1.78 (0.8) | 2.16 (2.0) | 1.86 (2.0) |
| S-Oxybutynin | 5.03 (3.2) | 3.67 (2.1) | 3.29 (2.7) | 2.80 (2.7) |
| R-Desethyloxybutynin | 23.0 (11.0) | 16.2 (6.0) | 27.8 (22) | 20.8 (22) |
| S-Desethyloxybutynin | 13.3 (7.9) | 10.3 (6.1) | 12.2 (6.8) | 9.13 (7.5) |
a – 10 mg: n=3; 15 mg: n=6
b – 10 mg: n=5; 15 mg: n=2
The pharmacokinetic parameters (Cmax and AUC) of oxybutynin and desethyloxybutynin are dose proportional following administration of 5-20 mg of oxybutynin prolonged release tablet. Steady state oxybutynin plasma concentrations are achieved by Day 3 of repeated dosing, with no observed change in oxybutynin and desethyloxybutynin pharmacokinetic parameters over time. These characteristics support linearity in the pharmacokinetics for oxybutynin.
Pre-clinical data reveal no special hazard for humans based on studies for acute toxicology, repeat dose toxicity, genotoxicity, carcinogenic potential and local toxicity. At a concentration of 0.4 mg/kg/day oxybutynin administered subcutaneously, the occurrence of organ anomalies is significantly increased, but is observed only in the presence of maternal toxicity. In the absence of understanding the association between maternal toxicity and developmental effect, the relevance to human safety cannot be addressed. In the subcutaneous fertility study in rats, while no effects were reported in males, in females, fertility was impaired and a NOAEL (no observed adverse effect level) of 5 mg/kg was identified.
The active substance oxybutynin is persistent in the environment.
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