4-[(2-ブロモ-4,5-ジメトキシフェニル)メチル]-4-[2-[2-(6,6-ジメチルビシクロ[3.1.1]ヘプタン-2-イル)エトキシ]エチル]モルホリニウム

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

Pinaverium

DILI Positive

DOI:10.1016/j.drudis.2019.09.022

A - Alimentary tract and metabolism

QA - Alimentary tract and metabolism

Pinaverium is a selective and specific voltage-dependent calcium channel blocker located on intestinal smooth muscle cells to inhibit calcium influx. It mediates various effects on the GI tract: it causes oesophageal, gastric and duodenal relaxation, relaxes the colon and intestines, inhibits colonic motility in response to food, hormonal or pharmacological stimuli, accelerates gastric emptying, and reduces contractions of the gallbladder and phasic contractions of sphincter of Oddi. At higher concentrations, pinaverium also exhibits very weak anticholinergic effects but is not shown to display vasodilatory or anti-arrythmic actions.

Pinaverium interacts with the 1,4-dihydropyridine binding sites on voltage dependent L-type calcium channels located on GI smooth muscle cells in a competitve manner. The binding site is located in the alpha 1S subunit and pinaverium most likely antagonizes the action of calcium ions by stabilizing a non-conducting channel state. Pinaverium inhibits smooth muscle contractions of the GI tract by inhibiting inward calcium current and calcium influx. It is suggested that pinaverium may be able to bind to both closed or inactivates states of the calcium channel with similar affinity.

A class of drugs that act by selective inhibition of calcium influx through cellular membranes.

Agents that inhibit the actions of the parasympathetic nervous system. The major group of drugs used therapeutically for this purpose is the MUSCARINIC ANTAGONISTS.

After oral administration, pinaverium is poorly absorbed (5-10%) followed by uptake by liver. Poor absorption is due to its highly polar quaternary ammonium group and high molecular weight, which limits extensive diffusion across all cell membranes and promotes its selectivity towards the gastrointestinal tracts []. Peak plasma concentration is reached within one hour after administration and the absolute oral bioavailability is reported to be less than 1%.

Pinaverium is predominantly eliminated into feces.

It is selectively distributed to the digestive tract due to poor absorption and marked hepatobiliary excretion.