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The pharmacokinetics of tritiated hexahydrosila-difenidol ([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 [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% of the 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 [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 well as by tissue distribution measurement the highest levels 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. [ABSTRACT FROM AUTHOR]

The M1 potency (decrease in neurogenic response) of carbachol, oxotremorine, muscarine, arecaidine propargly ester (APE) and 4-(4-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium iodide (4-Cl-McN-A-343) in rabbit field-stimulated vas deferens (prostatic segments) increased up to 15-fold when calcium was lowered (3.5-1.0 nM). The M2 receptor-mediated increase in twitch height in response to carbachol and the M1 affinity of pirenzepine were independent of calcium concentration (2.5 and 1.0 mM). Thus, prostatic segments of rabbit vas deferens can be used successfully at 1.0 mM calcium to determine M1 potencies of agonists and M1 affinities of antagonists without counteracting stimulation of M2 receptors.