Comparative penetration of glycopyrrolate and atropine across the blood-brain and placental barriers in anesthetized dogs

Abstract

The levels of 14C-glycopyrrolate, a quaternary ammonium anticholinergic agent, appearing in cerebrospinal fluid (CSF) and serum (S) following a single intravenous dose of 0.1 mg/kg were determined in mongrel dogs during barbiturate anesthesia and compared with levels reached in dogs treated with similar doses of 3H-atropine. Presence of each anticholinergic drug in the peripheral circulation was confirmed by antagonism of the depressor response to intravenously administered acetylcholine. Ten minutes after drug injection, CSF levels of 3H-atropine averaged 10.3 ± 3.1 ng/ml, whereas 14C-glycopyrrolate CSF levels were restricted to 0.9 ± 0.4 ng/ml. Peak CSF/S concentration ratios for 3H-atropine averaged 0.87, vs. a mean ratio of 0.1 for 14C-glycopyrrolate within the four-hour observation period. Peripheral anticholinergic activity produced by glycopyrrolate was of the same order as that seen with the equivalent dose of atropine. In pregnant barbiturate-anesthetized dogs peak mean fetal serum (FS) levels of 13 ± 1.5 ng/ml occurred 10 min after a single intravenous dose of 0.1 mg/kg 3H-atropine administered to the mother, and represented 30 per cent of the corresponding maternal serum (MS) concentration. 14C-Glycopyrrolate-treated dogs showed peak mean FS levels of 0.63 ± 0.7 ng/ml four hours after administration. The maximum FS/MS concentration ratio observed within the four-hour post-drug period for 3H-atropine was 1.0, vs. 0.04 for 14C-glycopyrrolate. Anticholinergic effects in the mother were significantly greater with glycopyrrolate than with identical doses of atropine. These studies show that glycopyrrolate is a selective peripheral anticholinergic agent, in that it is more resistant than atropine to penetration across the blood-brain and placental barriers.