Drug distribution in dog brain studied by positron emission tomography

Abstract

We used positron emission tomography to monitor the distribution of radioactivity in dog brain and muscle following i.v. administration of 11C-labelled antipyrine, imipramine, and quinidine. Twenty-five sequential scans of a transaxial slice of the head were performed within 90 min; radioactivity in plasma was measured in a gamma-counter. Following i.v. injection of [11C]antipyrine (50 mg kg-1; 9-68 mCi; n = 10), the decay of plasma activity was accompanied by rapid uptake in brain and variable uptake in muscle, immediately followed by a redistribution leading to equalization of the radioactivity in the tissues. Administration of [11C]imipramine (4 mg kg-1; 30-110 mCi; n = 8) was followed by a rapid build-up of a sustained gradient between high brain, and low plasma and muscle radioactivity. After i.v. injection of [11C]quinidine (1 mg kg-1; 11-87 mCi; n = 10), radioactivity in brain was low, with higher activity in plasma and muscle throughout the experiment. Positron emission tomography thus revealed for each drug a distinct pattern of distribution consistent with established properties of the compounds. This technique seems promising for the study of early drug distribution, notwithstanding certain limitations.

Impact of quinidine on plasma and cerebrospinal fluid concentrations of codeine and morphine after codeine intake

“…2). This is in line with the observations previously made in the dog (Hiatt et al 1945;Agon et al 1988)• However, quinidine does penetrate the barrier and is found at a low concentration (10-15 nmol. 1-1) in the cerebrospinal fluid.…”

“…Hiatt and Quinn found that cerebrospinal fluid/plasma and brain tissue/plasma concentration ratios of quinidine were 50-100 times lower than liver tissue/plasma ratio in dogs after a 2 h intravenous infusion of quinidine. The positron emission tomography study by Agon et al (1988) was also performed in dogs and showed a similar relationship between the plasma and brain levels of quinidine. Codeine is O-demethylated to morphine in brain tissue from rats (Chen et al 1990).…”

“…In combination with a weak effect of non-transformed codeine, this might have been able to increase the pain threshold significantly. Another possible explanation relates to observations indicating that quinidine penetrates the blood brain barrier poorly (Hiatt and Quinn 1945;Agon et al 1988). Hiatt and Quinn found that cerebrospinal fluid/plasma and brain tissue/plasma concentration ratios of quinidine were 50-100 times lower than liver tissue/plasma ratio in dogs after a 2 h intravenous infusion of quinidine.…”