Pharmacokinetics of an oral once-a-day controlled-release oxybutynin formulation compared with immediate-release oxybutynin

Oxybutynin is used for the treatment of urge urinary incontinence. In this randomized, open-label, two-way crossover, multiple-dose study, the pharmacokinetics of a once-daily, controlled-release formulation, OROS oxybutynin chloride, was compared with that of immediate-release (IR) oxybutynin (Ditropan). Thirteen healthy female volunteers received three 5 mg OROS oxybutynin chloride tablets once daily for 4 days or IR oxybutynin 5 mg administered every 8 hours for 4 days. On day 1, with OROS oxybutynin chloride, mean plasma concentrations rose slowly over approximately 6 hours following dosing (mean Cmax 4.2 ng/mL) and remained fairly constant over the 24-hour dosing interval, whereas with IR oxybutynin, mean plasma concentrations rose rapidly within the first hour after dosing (mean Cmax 12.0 ng/mL), then declined. The mean oxybutynin degree of fluctuation was much lower for OROS oxybutynin chloride (78%) than for IR oxybutynin (371%). For both formulations, the plasma concentration-time profiles for the metabolite N-desethyloxybutynin paralleled those of oxybutynin but at higher concentrations. Steady-state oxybutynin concentrations were achieved by day 3 for both formulations. Mean area under the concentration-time curve (AUC) values for both oxybutynin and its metabolite were similar between day 1 and day 4 for each treatment, suggesting time-invariant pharmacokinetics. With OROS oxybutynin chloride, mean relative bioavailability was higher (153%) for oxybutynin and lower (69%) for N-desethyloxybutynin compared with IR oxybutynin. This increased bioavailability may be due to reduced first-pass metabolism; within 3 to 5 hours after dosing, OROS systems are thought to reach the colon, where cytochrome P450-mediated oxidation (oxybutynin's primary metabolic pathway) may be less extensive than in the small intestine. Fewer subjects reported any adverse event with OROS oxybutynin chloride than with IR oxybutynin (including dry mouth, oxybutynin's most frequently reported anticholinergic adverse effect).     

Extended-release oxybutynin

Extended-release oxybutynin (Ditropan XL) uses an osmotic system (OROS) to deliver a controlled amount of oxybutynin chloride into the gastrointestinal tract over a 24-hour period when taken once daily. Oxybutynin binds to M3 muscarinic receptors on the detrusor muscle of the bladder, preventing acetylcholinergic activation and relaxing the muscle. Mean peak plasma concentrations are lower with extended-release oxybutynin 15mg once daily than with conventional immediate-release oxybutynin 5mg taken 3 times daily. Relative bioavailabilities of parent drug and metabolite N-desethoxybutynin are 153 and 69%, respectively, for extended-release oxybutynin when compared with immediate-release oxybutynin. In short (< or =6 weeks) randomised, double-blind clinical trials of patients with detrusor instability, extended-release oxybutynin 5 to 30mg once daily significantly reduced the mean weekly number of urge incontinence episodes by 84 to 90%. Extended-release oxybutynin had similar efficacy to immediate-release oxybutynin. Adverse events reported by patients taking extended-release oxybutynin were dose-related anticholinergic effects, most frequently dry mouth, somnolence, constipation, blurred vision and dizziness. A large noncomparative study demonstrated that approximately two thirds of the patients prescribed extended-release oxybutynin for detrusor instability were still taking the medication 6 months later.     

Reproductive toxicity studies with oxybutynin hydrochloride

Oxybutynin hydrochloride, an anti-cholinergic/anti-spasmodic agent, was examined for its effect on fertility and peri-post natal development in the rat and its embryotoxic potential in the rat and rabbit. In the rat effects on reproductive performance included a slight increase in the incidence of foetal malformations, extended gestation period and impaired post natal performance of offspring. These findings occurred at dosages clearly associated with maternal toxicity. Oxybutynin hydrochloride did not exert an effect on reproductive processes in the rat at lower dosages or on embryonic and foetal development in the rabbit.     

A benefit-risk assessment of extended-release oxybutynin.

Oxybutynin is a muscarinic receptor antagonist, which has been available for a number of years in its original immediate-release (IR) formulation. While oxybutynin IR has proven effective for the treatment of overactive bladder, its extended use can be limited by adverse effects, particularly dry mouth. An extended-release (ER) formulation of oxybutynin based on the OROS system has recently become available, which allows once daily administration. In direct comparison to oxybutynin IR, oxybutynin ER has an increased oral bioavailability for the parent compound oxybutynin which is accompanied by a reduced bioavailability for the active metabolite N-desethyl-oxybutynin. The latter has been implicated in mediating a major part of the adverse effects of oxybutynin treatment. Two double-blind, placebo-controlled, randomised studies in patients with overactive bladder have demonstrated that oxybutynin ER has a similar efficacy as oxybutynin IR but with improved tolerability. This is in line with clinical pharmacological studies demonstrating a smaller impairment of saliva production with oxybutynin ER than with oxybutynin IR. Thus, the ER formulation of oxybutynin maintains the therapeutic benefits and concomitantly improves tolerability.     

Pharmacokinetics and pharmacodynamics of once-daily controlled-release oxybutynin and immediate-release oxybutynin

Oxybutynin is used to treat patients with urinary urgency, frequency, and urge incontinence. In this 2-way, multiple-dose, crossover study, the pharmacokinetics and pharmacodynamics of once-daily controlled-release oxybutynin were compared with immediate-release oxybutynin. Eighteen healthy male volunteers received one 15-mg controlled-release oxybutynin tablet once daily for 5 days or one 5-mg immediate-release oxybutynin tablet every 8 hours for 5 days. The washout period between treatments was > or =7 days. The mean steady-state AUC for oxybutynin following controlled-release oxybutynin treatment was higher (73.0 ng.h/mL) than following immediate-release oxybutynin treatment (53.6 ng.h/mL) (P = .0001). The mean C(max) was lower for controlled-release oxybutynin (5.7 ng/mL) than for immediate-release oxybutynin (7.5 ng/mL) (P = .0051), with a smaller fluctuation in oxybutynin plasma concentration for controlled-release oxybutynin (135.6%) than for immediate-release oxybutynin (319.3%) (P = .0001). Mean stimulated saliva output was greater for controlled-release oxybutynin, and mean dry mouth severity was less than immediate-release oxybutynin.     

Poisoning with Amitraz

Amitraz, an insecticide and veterinary medicine, has been available in many countries since 1974 but reports of poisoning with it have only become prominent in the last 7 years. The vast majority of cases have occurred in Turkey and have involved children. The data available, both human and animal, do not allow clear separation of the features of toxicity of amitraz from those of the hydrocarbon solvents in which it is commonly dissolved. Amitraz stimulates α₂-adrenoceptors resulting in impairment of consciousness, respiratory depression, convulsions, bradycardia, hypotension, hypothermia and hypoglycaemia. Even the most severely poisoned patients recover with nothing more than intensive care; only one possible death has been documented. Animal studies indicate that the α₂-adrenoceptor antagonists, yohimbine and atipamezole, can reverse amitraz-induced toxicity but they have not been assessed in poisoned humans.     

Poisoning with amitraz

Amitraz, an insecticide and veterinary medicine, has been available in many countries since 1974 but reports of poisoning with it have only become prominent in the last 7 years. The vast majority of cases have occurred in Turkey and have involved children. The data available, both human and animal, do not allow clear separation of the features of toxicity of amitraz from those of the hydrocarbon solvents in which it is commonly dissolved. Amitraz stimulates alpha 2-adrenoceptors resulting in impairment of consciousness, respiratory depression, convulsions, bradycardia, hypotension, hypothermia and hypoglycaemia. Even the most severely poisoned patients recover with nothing more than intensive care; only one possible death has been documented. Animal studies indicate that the alpha 2-adrenoceptor antagonists, yohimbine and atipamezole, can reverse amitraz-induced toxicity but they have not been assessed in poisoned humans.     

Formulation study of oxybutynin patches

The present feasibility study was designed to obtain a monolayer patch containing oxybutynin (OXY) avoiding chemical permeation enhancers. The highest flux was obtained with a polydimethylsiloxane matrix patch. Because OXY crystals were detected in the matrix within a week, two amino methylmethacrylate copolymers (Eudragit E or Eudragit RS) were used as OXY crystallization inhibitors. A preliminary in vivo study indicated that flux from the stabilized patches had to be increased about 30-40%. This goal was reached by occlusion with a polyethylene layer.     

Poisoning with a traditional remedy containing potassium dichromate.

A fatal case of potassium dichromate ingestion is documented. A retrospective review of serum and organ levels of chromium demonstrates that charcoal haemoperfusion, peritoneal and haemodialysis are ineffective therapies for the toxin. Other treatments for this poisoning are reviewed, the poor prognosis of dichromate ingestion, and the paucity of effective therapy underlined. The application of dichromates in traditional medications is briefly discussed; this is a toxin which may be more prevalent than previously thought. It is proposed that the exposure limits of dichromate be more widely publicised.     

Transdermal oxybutynin: a review

Overactive bladder is a common and disabling problem. The mainstay of pharmacological treatment is with oral anticholinergic drugs. Anticholinergic side effects are common and include dry mouth and constipation. Compliance is limited by these side effects. Transdermal administration of oxybutynin has been shown to be as effective as oral treatment while minimising the anticholinergic side effects. Skin reactions occur frequently, necessitating changes of application site. Despite this, the preparation is a useful element in the armamentarium to treat overactive bladder. It is likely to be particularly useful in those in whom side effects of oral medication are intolerable or in whom oral administration of drug is not possible. Here, the pharmacokinetics, pharmacodynamics, efficacy and safety of transdermal oxybutynin are reviewed.     

Characterization of the oxybutynin antagonism of drug-induced spasms in detrusor.

Oxybutynin chloride exerts a moderate anticholinergic effect on rabbit detrusor in vitro, which is reversible and competitive in nature (KB = 4.7 x 10(-9), and midway in potency between atropine and papaverine. In addition, oxybutynin strongly antagonizes BaCl2-induced spasms of detrusor with a potency equivalent to that of papaverine and 10 times that of atropine. This musculotropic spasmolytic effect is slightly greater in rabbit than human or monkey tissue, and noncompetitive (pD2 = 5.5). This direct relaxant effect, unlike that of papaverine, is not mediated by the inhibition of tissue phosphodiesterase, but probably reflects oxybutynin's local anesthetic properties and associated effects on Ca++ fluxes and binding.