Lipophilicity and brain disposition of clonidine and structurally related imidazolidines

Abstract

The apparent partition coefficients (P') of clonidine and 27 of its structurally related imidazolidines were determined in the octanol/buffer (pH = 7.4) system as a measure of lipophilic behaviour. Lipophilicity of the imidazolidines is limited to the free bases and the principle of additivity is valid for this series of structurally similar compounds. Brain concentrations of clonidine and a number of its derivatives, achieved at the moment of maximal decrease in blood pressure, were determined following intravenous administration of anaesthetized rats. These brain concentrations represent the maximally attainable values. The ratio of log brain concentration/dose administered intravenously, log (Cbrain/Ci.v.), was employed as a measure of the penetration ability of the imidazolidines into the brain. The octanol/buffer (pH = 7.4) system proved a satisfactory reference model in order to describe the transport process of the present imidazolidines from the blood to the brain. The penetration ability of these compounds into the brain could be expressed mathematically by a highly significant, parabolic relationship in log P'. Ideal lipophilic character for optimal brain concentrations is connected with a log P' value of 2.16.

Clonidine Distribution in the Rat: Temporal Relationship Between Tissue Levels and Blood Pressure Response

“…This reflects the relatively high lipophilicity of clonidine (Timmermans, Brands & Van Zwieten, 1977). Regional variations in clonidine distribution in the brain were not pronounced at the peak of the hypotensive effect.…”

Structure‐activity Relationships of Clonidine‐ and Tolazoline‐like Compounds at Histamine and Α‐adrenoceptor Sites

“…Physicochemical data for 15 of the imidazolidines studied (Table 1) was available from the work of Timmermans, Brands & van Zwieten (1977a) and Timmermans & van Zwieten (1978). Linear, multiple and polynomial regression analyses were used to determine possible correlations between pD'2 values (pD2 values corrected for the degree of ionization at pH 7.4) with pKa, log P (octanolphosphate buffer partition coefficient, pH 7.4) or (log p)2.…”

Efeitos da associação da clonidina à ropivacaína na anestesia peridural

“…Após administração por via peridural, a clonidina é rapidamente absorvida, atingindo pico de concentração plasmáti-ca no sangue arterial, dentro de 10 minutos, e no sangue venoso, em 30 a 45 minutos 2 . Em função da alta lipossolubilidade, atravessa a barreira hematoencefálica, distribuindo-se amplamente no sistema nervoso central (SNC), onde interage com os receptores a 2 -adrenérgicos, em nível espinhal e supra-espinhal 24 .…”

“…In our study, perioperative sedative effect of epidural clonidine was clinically significant with a high number of clonidine group patients (66.67%) presenting consciousness level score 3 (sleepy by easily awakened). After epidural administration, clonidine is rapidly absorbed reaching peak plasma concentration in arterial blood within 10 minutes and in venous blood in 30 to 45 minutes interacts with a 2 -adrenergic receptors at spinal and supraspinal level 24 . The activation of a 2 -adrenergic receptors in the CNS, with decreased norepinephrine release, is the cause of the sedative effects of such receptors agonists 25 .…”