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Ditropan

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Ditropan

CLINICAL PHARMACOLOGY

Oxybutynin chloride exerts a direct antispasmodic effect on smooth muscle and inhibits the muscarinic action of acetylcholine on smooth muscle. Oxybutynin chloride exhibits only one fifth of the anticholinergic activity of atropine on the rabbit detrusor muscle, but four to ten times the antispasmodic activity. No blocking effects occur at skeletal neuromuscular junctions or autonomic ganglia (antinicotinic effects).

Oxybutynin chloride relaxes bladder smooth muscle. In patients with conditions characterized by involuntary bladder contractions, cystometric studies have demonstrated that oxybutynin chloride increases bladder (vesical) capacity, diminishes the frequency of uninhibited contractions of the detrusor muscle, and delays the initial desire to void. Oxybutynin chloride thus decreases urgency and the frequency of both incontinent episodes and voluntary urination.

Antimuscarinic activity resides predominately in the R-isomer. A metabolite, desethyloxybutynin, has pharmacological activity similar to that of oxybutynin in in vitro studies.

Pharmacokinetics

Absorption

Following oral administration of DITROPAN, oxybutynin is rapidly absorbed achieving Cmax within an hour, following which plasma concentration decreases with an effective half-life of approximately 2 to 3 hours. The absolute bioavailability of oxybutynin is reported to be about 6% (range 1.6 to 10.9%) for the tablets. Wide interindividual variation in pharmacokinetic parameters is evident following oral administration of oxybutynin.

The mean pharmacokinetic parameters for R- and S-oxybutynin are summarized in Table 1. The plasma concentration-time profiles for R- and S-oxybutynin are similar in shape; Figure 1 shows the profile for R-oxybutynin.

Table 1 : Mean (SD) R-and S-Oxybutynin Pharmacokinetic Parameters Following Three Doses of DITROPAN 5 mg Administered every 8 Hours (n=23)

Parameters (units) R-Oxybutynin S-Oxybutynin
Cmax (ng/mL) 3.6 (2.2) 7.8 (4.1)
Tmax (h) 0.89 (0.34) 0.65 (0.32)
AUCt (ng•h/mL) 22.6 (11.3) 35.0 (17.3)
AUCinf (ng?h/mL) 24.3 (12.3) 37.3 (18.7)

Figure 1: Mean R-oxybutynin plasma concentrations following three doses of DITROPAN 5 mg administered every 8 hours for 1 day in 23 healthy adult volunteers

Mean R-oxybutynin plasma concentrations - Illustration

DITROPAN steady-state pharmacokinetics were also studied in 11 pediatric patients with detrusor overactivity associated with a neurological condition (e.g., spina bifida). These pediatric patients were on DITROPAN tablets with total daily dose ranging from 7.5 mg to 15 mg (0.22 to 0.53 mg/kg). Overall, most patients (86.9%) were taking a total daily DITROPAN dose between 10 mg and 15 mg. Sparse sampling technique was used to obtain serum samples. When all available data are normalized to an equivalent of 5 mg twice daily DITROPAN, the mean pharmacokinetic parameters derived for R- and S-oxybutynin and R- and S-desethyloxybutynin are summarized in Table 2. The plasma-time concentration profiles for R- and Soxybutynin are similar in shape; Figure 2 shows the profile for R-oxybutynin when all available data are normalized to an equivalent of 5 mg twice daily.

Table 2 Mean ± SD R- and S-Oxybutynin and R- and S-Desethyloxybutynin Pharmacokinetic Parameters In Children Aged 5-15 Following Administration of 7.5 mg to 15 mg Total Daily Dose of DITROPAN Tablets (N=11)
All Available Data Normalized to an Equivalent of DITROPAN Tablets 5 mg BID or TID at Steady State

  R-Oxybutynin S-Oxybutynin R-Desethyloxybutynin S-Desethyloxybutynin
Cmax* (ng/mL) 6.1± 3.2 10.1 ± 7.5 55.4 ± 17.9 28.2 ± 10.0
Tmax (hr) 1.0 1.0 2.0 2.0
AUC† (ng.hr/mL) 19.8 ± 7.4 28.4 ± 12.7 238.8 ± 77.6 119.5 ± 50.7
*Reflects Cmax for pooled data
†AUC0-end of dosing interval

Figure 2: Mean steady-state (±SD) R-oxybutynin plasma concentrations following administration of total daily DITROPAN Tablet dose of 7.5 mg to 15 mg (0.22 mg/kg to 0.53 mg/kg) in children 5-15 years of age. – Plot represents all available data normalized to the equivalent of DITROPAN 5 mg BID or TID at steady state

Mean steady-state (±SD) R-oxybutynin plasma concentrations - Illustration

Food Effects

Data in the literature suggests that oxybutynin solution co-administered with food resulted in a slight delay in absorption and an increase in its bioavailability by 25% (n=18).1

Distribution

Oxybutynin is widely distributed in body tissues following systemic absorption. The volume of distribution is 193 L after intravenous administration of 5 mg oxybutynin chloride. 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.

Metabolism

Oxybutynin is metabolized primarily by the cytochrome P450 enzyme systems, 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.

Excretion

Oxybutynin is extensively metabolized by the liver, 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 desethyloxybutynin.

Clinical Studies

DITROPAN was well tolerated in patients administered the drug in controlled studies of 30 days' duration and in uncontrolled studies in which some of the patients received the drug for 2 years.

REFERENCES

1. Yong C et al. Effect of Food on the Pharmacokinetics of Oxybutynin in normal subjects. Pharm Res. 1991; 8 (Suppl.): S-320.

Last reviewed on RxList: 4/2/2012
This monograph has been modified to include the generic and brand name in many instances.

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