Pharmacokinetic properties of the antimuscarinic drug [3H]-hexahydro-sila-difenidol in the rat

Abstract

Summary. The pharmacokinetics of tritiated hexahydrosila-difenidol ([ 3 H]-HHSiD) were examined in rats. Furthermore, the distribution of radioactivity was studied by means of whole body autoradiography.After i. v. administration of 2.9 mg/kg HHSiD plus [ 3 H]-HHSiD to anaesthetized rats bearing a catheter implanted in the ductus choledochus and receiving a mannitol infusion, HHSiD was rapidly distributed and metabolized. Only 5% ofthe radioactivity was recovered in blood after 23 s and 0.4% after 2.5 h. 64% of the plasma radioactivity could be extracted with hexane from the samples taken 23 s after administration. 52% of the radioactivity was eliminated within 2.5 h, 13% by urinary and 39% by biliary excretion. Following oral administration of 8.6 mg/kg HHSiD plus [3 H]-HHSiD there was an absorption of approximately one fourth of the administered radioactivity within 4 h. By means of whole body autoradiography (i. v. injection) as weil as by tissue distribution measurement the highest Ievels of radioactivity were found in bile, urine, lung, kidney, adrenals, liver and .pancreas. Thus, after i. v. administration to rats HHSiD is rather quickly distributed, metabolized and excreted. This explains its low antimuscarinic potency in vivo.

Cardiopulmonary actions of muscarinic receptor subtypes in the newborn dog

“…Although this antagonist is selective for M 3 receptors, the magnitude of the selectivity is not great, as illustrated by the HR/RL ED 50 ratio (Table 2) and in vitro studies of selectivity (Dorje et al 1991;Waelbroeck et al 1991;Buckley et al 1989;Eltze and Galvan 1994). Furthermore, the potency of the parent compound in vivo has been suggested to be less than expected as a result of rapid metabolism (Rettenmayer et al 1990). Although highly selective antagonists of the M 3 muscarinic receptor subtype are not yet available (Dorje et al 1991;Waelbroeck et al 1991;Buckley et al 1989;Eltze and Galvan 1994), current consensus suggests that M 3 antagonists would eliminate the untoward effects of nonspecific antagonists such as ipratropium bromide (Barnes 1993a;Loenders et al 1992).…”