Pharmacokinetics

Cisapride is metabolized mainly via the cytochrome P450 3A4 enzyme. Cisapride is extensively metabolized; unchanged drug accounts for less than 10% of urinary and fecal recovery following oral administration. Norcisapride, formed by N-dealkylation, is the principal metabolite in plasma, feces, and urine. Cisapride is rapidly absorbed after oral administration; peak plasma concentrations are reached 1 to 1.5 hours after dosing. The absolute bioavailability of cisapride is 35-40%. When gastric acidity was reduced by high dose histamine H₂ receptor blocker and sodium bicarbonate in fasting subjects, there was a decrease in the rate, and to a lesser degree the extent, of cisapride tablet absorption. (This has not been established for the suspension.) Cisapride binds to an extent of 97.5-98% to plasma proteins, mainly to albumin. The volume of distribution of cisapride is about 180 L, indicating extensive tissue distribution.

The plasma clearance of cisapride is about 100 ml/min. The mean terminal half-life reported for cisapride ranges from 6 to 12 hours; longer half-lives, up to 20 hours, have been reported following intravenous (IV) administration.

There was no unusual drug accumulation due to time-dependent or non-linear changes in pharmacokinetics. After cessation of the repeated dosing, the elimination half-lives (8 to 10 hr) were in the same order as after single dosing. The degree of accumulation of cisapride and/or its metabolites may be somewhat higher in patients with hepatic or renal impairment and in elderly patients compared to young healthy volunteers, but the differences are not consistent. Dose adjustments are recommended in patients with hepatic impairment. (See DOSAGE AND ADMINISTRATION.)

The pharmacokinetics of cisapride in pediatric patients are not well characterized. Therefore, it is unknown if the dose-response relationship in the adult population can be extrapolated to the pediatric population. (See PRECAUTIONS, Pediatric Use.)

Pharmacodynamics

The onset of pharmacological action of cisapride is approximately 30 to 60 minutes after oral administration.

Cisapride promotes gastric motility. The mechanism of action of cisapride is thought to be primarily enhancement of release of acetylcholine at the myenteric plexus. Cisapride does not induce muscarinic or nicotinic receptor stimulation, nor does it inhibit acetylcholinesterase activity. It is less potent than metoclopramide in dopamine receptor-blocking effects in rats. It does not increase or decrease basal or pentagastrin-induced gastric acid secretion.

In vitro studies have shown that cisapride is a serotonin-4 (5-HT₄) receptor agonist.

Electrophysiological studies in in vivo anesthetized guinea pig and rabbit models and in vitro isolated rabbit Purkinje fibers and ventricular papillary muscle and isolated rabbit ventricular myocyte models, have shown that cisapride prolonged cardiac repolarization without slowing conduction by selectively blocking the rapid component of the delayed rectifying K⁺ current (l_kr) which leads to a lengthening of the action potential (QT Syndrome).

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