Premium
Pharmacokinetics of anticholinergic drugs and brain muscarinic receptor alterations in streptozotocin diabetic rats
Author(s) -
Nakashima Emi,
Ishizaki Junko,
Takeda Masami,
Matsushita Ryo,
Yokogawa Koichi,
Ichimura Fujio
Publication year - 1993
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.2510140804
Subject(s) - muscarinic acetylcholine receptor , endocrinology , medicine , streptozotocin , chemistry , anticholinergic , muscarinic acetylcholine receptor m4 , muscarinic acetylcholine receptor m3 , muscarinic antagonist , receptor , muscarinic acetylcholine receptor m1 , muscarinic acetylcholine receptor m2 , diabetes mellitus
We studied the effects of experimental diabetes on the pharmacokinetics of biperiden (BP) and scopolamine (SP) and brain muscarinic receptor alterations in rats after the injection of streptozotocin (STZ) (60mg kg −1 i.v.). The serum levels of BP and SP differed significantly between the rats 14 weeks after the STZ treatment and age‐matched control rats. The values of total body clearance (CL tot ) of BP and SP were significantly increased by STZ treatment. The values of volume of distribution ( V dss ) of SP were slightly increased in the STZ‐treated rats, although V dss of BP was decreased. Because of the high lipophilicity of BP, V dss of BP may be decreased due to the reduced fat tissue volume caused by STZ treatment. The density of the muscarinic receptors in whole brain was measured by a radioligand receptor binding assay using [ 3 H]‐quinuclidinyl‐benzylate ([ 3 H]‐QNB). The density in the diabetic rats two weeks after the STZ treatment was significantly decreased compared to age‐matched control rats. However in the diabetic rats 14 weeks after the STZ treatment, there was no difference in the density of muscarinic receptors. The IC 50 of muscarinic antagonist for the binding of [ 3 H]‐QNB to the receptor did not change on STZ treatment. Modulation of the receptor following repeated anticholinergic drug exposure was studied. In control rats, the number of muscarinic receptors in the brain increased by 6.9% on chronic treatment with BP for two weeks. When diabetic rats were treated with BP and SP, the number of muscarinic receptors in the brain increased by 9.6% and 33.8%, respectively.