Alkyl-substituted silica gel as a carrier in the controlled release of dexmedetomidine.

The effect of alkyl substitution of the silica xerogel matrix on the release rate of dexmedetomidine was evaluated. Silica sol was processed by either casting or spray drying. When the reaction precursor tetraethylorthosilicate (TEOS) was partially substituted with tri- or dialkoxysilane, the release of dexmedetomidine and degradation of the matrix were decreased compared with 100% TEOS-based gel. Increasing the number or length of the organic groups attached to silicon, modified the silica gel structure and reduced the release rate of dexmedetomidine from monoliths. The release of dexmedetomidine from alkyl-substituted silica gel microparticles, however, showed a burst in drug release. Subcutaneously administered silica xerogel matrices (manufactured by casting, containing 25 mol% dimethyldiethoxysilane at two different doses of dexmedetomidine) were studied in dogs. Sustained delivery of dexmedetomidine was obtained for at least 48 h.

Buccal delivery of an alpha 2-adrenergic receptor antagonist, atipamezole, in humans.

OBJECTIVE: To evaluate the pharmacokinetics, systemic effects and clinical applicability of buccally administered atipamezole in healthy volunteers. METHODS: The study was carried out in two parts. In the first part, spray preparations of atipamezole hydrochloride in water/alcohol (50/50) solution were applied on buccal mucosa of six volunteers. Single doses of 5, 10, 20, and 40 mg atipamezole hydrochloride were administered in ascending order during separate sessions. In the second part, nine subjects received single 20 mg doses as buccal spray, intravenous infusion, or oral solution in randomized order. RESULTS: Values for area under the concentration-time curve for atipamezole (mean +/- SD) ranged from 26 +/- 4 ng x hr/ml after 5 mg to 112 +/- 21 ng x hr/ml after 40 mg and peak concentrations ranged from 11 +/- 3 ng/ml after 5 mg to 38 +/- 9 ng/ml after 40 mg. Individual peak concentrations were mainly measured at 30 and 60 minutes after administration. Mean elimination half-lives were approximately 1 1/2 hours after every treatment. In part two, a mean bioavailability of 33% was calculated for buccal administration (compared with intravenous), whereas systemic availability after an oral dose was < 2%. After intravenous administration the mean total clearance, apparent volume of distribution, and elimination half-life were 1.2 L/hr/kg, 2.9 L/kg, and 1.8 hours, respectively. The intravenous administration of 20 mg atipamezole hydrochloride produced a fivefold elevation in mean plasma norepinephrine concentration, a slight and short-lasting elevation in blood pressure and, in most subjects, increased tension, alertness and restlessness, and sweating. After buccal administration, some subjects reported short-lasting restlessness or tension after the 20 and 40 mg doses. No significant changes in heart rate, blood pressure, or plasma catecholamines were observed. No effects were observed after swallowing of 20 mg atipamezole hydrochloride. The spray caused local reactions at buccal mucosa. Superficial white spots or areas were observed for several hours; these disappeared gradually. Subjects also reported transient numbness at the application site. CONCLUSION: Atipamezole hydrochloride is well absorbed systemically through oral mucosa. The oral bio-availability of atipamezole is negligible, probably because of extensive first-pass metabolism.

Atipamezole increases medetomidine clearance in the dog: an agonist-antagonist interaction.

Medetomidine, an alpha 2-adrenoceptor agonist, is a potent sedative and analgesic agent in the dog. When necessary, its action can be effectively antagonized by atipamezole. The present work was designed to study the effects of these drugs on each others' pharmacokinetics when a single intramuscular dose of medetomidine (50 micrograms kg-1) was followed by a dose of atipamezole (250 micrograms kg-1). Three different treatments were used: medetomidine alone, atipamezole alone, and atipamezole after medetomidine. Drug concentrations in plasma were measured by GC-MS. Statistical analysis of the results (ANOVA) revealed significant differences between treatments in the kinetic parameters of medetomidine. Atipamezole decreased the AUC of medetomidine from 41.3 to 28.6 ng h ml-1 (P = 0.005), t1/2 from 1.44 to 0.87 h (P = 0.015), and increased Cl from 21 to 31 ml min-1 kg-1 (P = 0.017). Differences in Vz did not reach statistical significance. The only statistically significant effects of medetomidine on the pharmacokinetics of atipamezole in this study were the slight decrease of Cl and Cmax as well as the increase of AUC. It is suggested that the large dose of medetomidine used caused haemodynamic changes, resulting in decreased hepatic circulation and slower drug metabolism. Antagonism by atipamezole restored the hepatic blood flow and, consequently, increased the elimination of medetomidine by biotransformation.

Systemic absorption and systemic effects of ocularly administered dexmedetomidine in rabbits.

Dexmedetomidine is a selective alpha 2-adrenoceptor agonist which has previously been shown to reduce the ocular pressure of normotensive rabbits as well as those with pressures artificially elevated by laser irradiation. In this study instillation of an equivalent hypotensive dose (12.5 micrograms) did not cause changes in heart rate, blood pressure, blood glucose or plasma catecholamine content even though dexmedetomidine could be detected in plasma. However, this dose given intravenously (i.v.) was also without effect. Higher ocular doses resulted in equivalent bradycardia and changes in blood glucose levels as when the dose was given i.v. These two parameters proved to be most sensitive indicators of systemic alpha 2-agonism, blood pressure did not change and plasma catecholamine levels were too low to be reliably assayed. It is concluded that when hypotensive doses of dexmedetomidine are instilled into the eye, intraocular concentrations are sufficiently high to exert pharmacological effects. As it is absorbed into the general circulation, it is diluted such that its systemic effects are minimal.

The pharmacokinetics and hemodynamic effects of intravenous and intramuscular dexmedetomidine hydrochloride in adult human volunteers.

BACKGROUND: Dexmedetomidine is an alpha 2 agonist with potential utility in clinical anesthesia for both its sedative and sympatholytic properties. METHODS: The pharmacokinetics and hemodynamic changes that occurred in ten healthy male volunteers were determined after administration of dexmedetomidine 2 micrograms/kg by intravenous or intramuscular route in separate study sessions. RESULTS: The intramuscular absorption profile of dexmedetomidine, as determined by deconvolution of the observed concentrations against the unit disposition function derived from the intravenous data, was biphasic. The percentage bioavailability of dexmedetomidine administered intramuscularly compared with the same dose administered intravenously was 73 +/- 11% (mean +/- SD). After intramuscular administration, the mean time to peak concentration was 12 min (range 2-60 min) and the mean peak concentration was 0.81 +/- 0.27 ng/ml. After intravenous administration of dexmedetomidine, there were biphasic changes in blood pressure. During the 5-min intravenous infusion of 2 micrograms/kg dexmedetomidine, the mean arterial pressure (MAP) increased by 22% and heart rate (HR) declined by 27% from baseline values. Over the 4 h after the infusion, MAP declined by 20% from baseline and HR rose to 5% below baseline values. The hemodynamic profile did not show acute alterations after intramuscular administration. During the 4 h after intramuscular administration, MAP declined by 20% and HR declined by 10%. CONCLUSIONS: The intramuscular administration of dexmedetomidine avoids the acute hemodynamic changes seen with intravenous administration, but results in similar hemodynamic alterations within 4 h.

Computer-controlled infusion of intravenous dexmedetomidine hydrochloride in adult human volunteers.

BACKGROUND: This investigation extended the pharmacokinetic analysis of our previous study, of intravenous dexmedetomidine in 10 healthy male volunteers, and prospectively tested the resulting compartmental pharmacokinetics in an additional six subjects using a computer-controlled infusion pump (CCIP) to target four different plasma concentrations of dexmedetomidine for 30 min at each concentration. METHODS: A three-compartment mamillary pharmacokinetic model best described the intravenous dexmedetomidine concentration versus time profile following the 5 min intravenous infusion of 2 micrograms/kg in our previous study. Nonlinear regression was performed using both two-stage and pooled data techniques to determine the population pharmacokinetics. The pooled technique allowed covariates, such as weight, age, and height of the subjects, to be incorporated into the nonlinear regression to test the hypothesis that these additional covariates would reduce the residual error between the measured concentrations and the predicted values. RESULTS: The addition of age, weight, lean body mass, and body surface area as covariates of the pharmacokinetic parameters did not improve the predictive value of the model. However, the model was improved when subject height was a covariate of the volume in the central compartment. The residual error in the pharmacokinetic model was markedly lower with the pooled versus the two-stage approach. The following pharmacokinetic values were obtained from the pooled analysis of the zero-order dexmedetomidine infusion: V1 = 8.05, V2 = 12.4, V3 = 175 (L), Cl1 = (0.0101*height [cm]) -1.33, Cl2 = 2.05, and Cl3 = 2.0 (L/min). Prospective evaluation of the pooled pharmacokinetic parameters using a computer-controlled infusion in six healthy volunteers showed the precision (average [(absolute error)/measured concentration]) of the CCIP to be 31.5% and the bias (average [error/measured concentration]) to be -22.4%. A pooled regression of the combined CCIP and zero-order data confirmed that the covariate, height (cm), was related in linear fashion to Cl1. A striking nonlinearity of dexmedetomidine pharmacokinetics related to concentration was observed during the CCIP infusion. The final pharmacokinetic values for the entire data set were: V1 = 7.99, V2 = 13.8, V3 = 187 (L), Cl1 = (0.00791*height [cm]) -0.927, Cl2 = 2.26, and Cl3 = 1.99 (L/min). CONCLUSIONS: Pharmacokinetics of dexmedetomidine are best described by a three-compartment model. Addition of age, weight, lean body mass, and body surface area do not improve the predictive value of the model. Additional improvement in CCIP accuracy for dexmedetomidine infusions would require magnification modification of the model based on the targeted concentration.

Pharmacodynamics and pharmacokinetics of intramuscular dexmedetomidine.

The pharmacodynamics and pharmacokinetics of intramuscular dexmedetomidine--a novel alpha 2-adrenergic receptor agonist under development for preanesthetic use--were studied in healthy male volunteers. Single intramuscular doses of dexmedetomidine (0.5, 1.0, and 1.5 microgram/kg) and placebo were administered to six subjects in a single-blind, multiple crossover study. Dexmedetomidine induced dose-related impairment of vigilance assessed both objectively and subjectively. The drug also caused moderate decreases in blood pressure and heart rate. Plasma norepinephrine was dose-dependently (maximum 89%) decreased. The intramuscular doses resulted in linearly dose-related plasma concentrations of dexmedetomidine. Pharmacokinetic calculations revealed a time to maximum concentration from 1.6 to 1.7 hours, an elimination half-life of 1.6 to 2.4 hours, an apparent total plasma clearance of 0.7 to 0.9 L/hr/kg, and apparent volume of distribution of 2.1 to 2.6 L/kg. The sedative effect of dexmedetomidine dissipated during the 6-hour observation time, but all other effects were still evident 6 hours after administration of the higher doses, paralleling the plasma concentration curves. The relationship of plasma concentrations of dexmedetomidine to pharmacodynamic variables was consistent with a linear pharmacodynamic model. The pharmacodynamic-pharmacokinetic profile of intramuscular dexmedetomidine may be suited to the proposed preanesthetic clinical use of this alpha 2-agonist.

Identification of detomidine carboxylic acid as the major urinary metabolite of detomidine in the horse.

Horse urine was investigated for metabolites by chromatography and mass spectrometry following the oral administration of the large animal analgesic sedative detomidine to two stallions and intravenous administration of [3H]-detomidine to a mare. Detomidine carboxylic acid and hydroxydetomidine glucuronic acid conjugate were identified in the urine after the oral doses. In addition, traces of free hydroxydetomidine were observed. About half of the radioactivity of [3H]-detomidine was excreted in the urine in 12 h after the i.v. dose (80 micrograms/kg). Most of the excretion occurred between 5 and 12 h in contrast to urine output which was highest 2-5 h after the dosing. The major radioactive metabolite in the urine was detomidine carboxylic acid. It comprised more than two thirds of the total metabolites in all the urine fractions collected. Its excretion profile was similar to that of total radioactivity. Hydroxydetomidine glucuronide was also excreted. It contributed 10-20% of the total metabolites in the urine. The free aglycone was only seen in the samples collected during the peak urine flow. A minor metabolite was tentatively characterized as the glucuronide of N-hydroxydetomidine.

Metabolism of toremifene in the rat.

Toremifene was labelled to a specific activity of about 20 microCi/mmol with tritium at positions 3 and 5 in the para-substituted phenyl ring. At these positions tritium is not eliminated within the metabolic pathways. A mixture of unlabelled and labelled toremifene (5 or 10 mg/kg, 5 microCi/mg) was given i.v. or p.o. to Sprague-Dawley rats. The elimination of radioactivity was followed up by collecting urine and feces daily for 13 days. The elimination of toremifene which was similar after p.o. and i.v. administration took place mainly in the feces. About 70% of the total radioactivity was eliminated within 13 days, of this amount more than 90% in the feces. All applied radioactivity could be detected in three separate fractions according to the oxidative state of the side chain when counted by Berthold TLC Linear Analyzer. Each fraction was further separated into single metabolites by TLC or HPLC. Altogether 9 metabolites were identified and almost all methanol-extractable components were identified. The main metabolic pathways in the rat were 4-hydroxylation and N-demethylation. The side chain was further oxidized to alcohols and carboxylic acids. Small amounts of unchanged toremifene were found in the feces both after p.o. and i.v. administration indicating biliary secretion.

Metabolism of detomidine in the rat. II. Characterisation of metabolites in urine.

In order to investigate the biotransformation of a new alpha 2-adrenoceptor agonist, detomidine, metabolites were isolated from rat urine by solid phase extraction and purified by TLC. The isolated compounds were structurally analysed by 1H-NMR, MS and GC-MS as such or as their methyl and/or silyl derivatives. In addition to detomidine, which was found in trace amounts, four major metabolites were identified: hydroxymethyldetomidine, the corresponding O-glucuronide, detomidine carboxylic acid, and detomidine mercapturate. Together the identified components make up about 80% of urinary detomidine derived compounds. On the basis of these findings a major biotransformation pathway could be suggested. The reaction sequence is initiated by a hydroxylation. Subsequent glucuronidation, glutathione conjugation or secondary oxidation divide the route into three branches each producing one of the other three identified metabolites.