Pharmacokinetics of dexmedetomidine during administration of vatinoxan in male neutered cats anesthetized with isoflurane.

Dexmedetomidine is an alpha-2 adrenoceptor agonist, and vatinoxan is an alpha-2 antagonist believed to poorly cross the blood-brain barrier in cats. Dexmedetomidine-vatinoxan combinations are of interest in anesthetized cats because the anesthetic sparing effect of dexmedetomidine may be preserved while vatinoxan attenuates the adverse cardiovascular effects of dexmedetomidine. The aim of this study was to characterize the pharmacokinetics of dexmedetomidine in cats during administration of isoflurane and vatinoxan. Six healthy adult male castrated cats were anesthetized with isoflurane in oxygen. Vatinoxan was administered using a target-controlled infusion system intended to maintain a plasma concentration of 4 µg/ml. Dexmedetomidine, 35 µg/kg was administered intravenously over 5 min. Plasma dexmedetomidine and vatinoxan concentrations were measured at selected time points ranging from prior to 8 hr after dexmedetomidine administration using liquid chromatography/tandem mass spectrometry. Compartment models were fitted to the time-concentration data using nonlinear mixed-effect modeling. A three-compartment model best fitted the data. Typical value (% interindividual variability) for the three-compartment volumes (ml/kg), the metabolic clearance and the two intercompartment distribution clearances (ml min-1 kg-1 ) were 168 (259), 318 (35), 1,425 (18), 12.4 (31), 39.1 (18), and 29.6 (17), respectively. Mean ± standard deviation plasma vatinoxan concentration was 2.6 ± 0.6 µg/ml.

Pharmacokinetics of vatinoxan in male neutered cats anesthetized with isoflurane.

OBJECTIVE: To characterize the pharmacokinetics of vatinoxan in isoflurane-anesthetized cats. STUDY DESIGN: Prospective experimental study. ANIMALS: A group of six adult healthy male neutered cats. METHODS: Cats were anesthetized using isoflurane in oxygen. Venous catheters were placed to administer the drug and sample blood. Vatinoxan, 1 mg kg-1, was administered intravenously over 5 minutes. Blood was sampled before and at various times during and up to 8 hours after vatinoxan administration. Plasma vatinoxan concentration was measured using liquid chromatography/tandem mass spectrometry. Compartment models were fitted to the time-concentration data using population methods and nonlinear mixed effect modeling. RESULTS: A three-compartment model best fitted the data. Typical value (% interindividual variability) for the three volumes (mL kg-1), the metabolic clearance and two distribution clearances (mL minute-1 kg-1) were 34 (55), 151 (35), 306 (18), 2.3 (34), 42.6 (25) and 5.6 (0), respectively. Hypotension increased the second distribution clearance to 10.6. CONCLUSION AND CLINICAL RELEVANCE: The pharmacokinetics of vatinoxan in anesthetized cats were characterized by a small volume of distribution and a low clearance. An intravenous bolus of 100 µg kg-1 of vatinoxan followed by constant rate infusions of 55 µg kg-1 minute-1 for 20 minutes, then 22 µg kg-1 minute-1 for 60 minutes and finally 10 µg kg-1 minute-1 for the remainder of the infusion time is expected to maintain the plasma concentration within 90%-110% of the plasma vatinoxan concentration previously shown to attenuate the cardiovascular effects of dexmedetomidine (25 µg kg-1) in conscious cats.

Cardiopulmonary effects of dexmedetomidine, with and without vatinoxan, in isoflurane-anesthetized cats.

OBJECTIVE: To characterize the cardiopulmonary effects of dexmedetomidine, with or without vatinoxan, in isoflurane-anesthetized cats. STUDY DESIGN: Randomized, crossover experimental study. ANIMALS: A group of six adult healthy male neutered cats. METHODS: Cats were instrumented during anesthesia with isoflurane in oxygen. Isoflurane end-tidal concentration was set to 1.25 minimum alveolar concentration (MAC). Dexmedetomidine was administered using a target-controlled infusion system to achieve and maintain 10 target plasma concentrations ranging from 0 to 40 ng mL-1. Furthermore, vatinoxan or an equivalent volume of saline was administered using a target-controlled infusion system to achieve and maintain a target plasma concentration of 4 µg mL-1. Isoflurane concentration was adjusted after each change in dexmedetomidine concentration to maintain a concentration equivalent to 1.25 MAC. Heart rate (HR), arterial blood pressure, central venous pressure (CVP), pulmonary artery pressure (PAP), pulmonary artery occlusion pressure (PAOP), body temperature, cardiac output, arterial and mixed-venous blood gas and pH and drug concentrations were measured. Additional variables were calculated from the measurements. RESULTS: Dexmedetomidine alone resulted in decreased HR, cardiac index, stroke index and oxygen delivery, and increased systolic, mean (MAP) and diastolic arterial pressure, CVP, PAP, PAOP, systemic vascular resistance index, rate-pressure product, left ventricular stroke work index and oxygen extraction ratio. Vatinoxan resulted in severe hypotension at target plasma dexmedetomidine concentrations <10 ng mL-1. Vatinoxan attenuated the cardiovascular effects of dexmedetomidine at the 10 and 20 ng mL-1 targets, but MAP could be maintained above 60 mmHg only when isoflurane concentration was <1.25 MAC. Less improvement in cardiovascular function was seen with vatinoxan at the 40 ng mL-1 target plasma dexmedetomidine concentration. CONCLUSIONS AND CLINICAL RELEVANCE: Vatinoxan, at the plasma concentration maintained in this study, attenuated the cardiovascular effects of dexmedetomidine in isoflurane-anesthetized cats. However, its administration resulted in hypotension, which may limit its clinical usefulness.

Effect of α2-adrenoceptor antagonism on the minimum alveolar concentration of isoflurane in cats.

OBJECTIVE: To characterize the effect of α2-adrenoceptor antagonism on the minimum alveolar concentration of isoflurane (MACISO) in cats. STUDY DESIGN: Prospective experimental study. ANIMALS: A group of five healthy adult male neutered cats. METHODS: Cats were anesthetized with isoflurane in oxygen and instrumented. MACISO was determined in duplicate in five cats, before and during administration of atipamezole (250 µg kg-1 followed by 250 µg kg-1 hour-1) using the bracketing technique and tail clamping. Estimates of MACISO obtained before and during administration of atipamezole were compared using a two-tailed paired t test. RESULTS: MACISO during atipamezole administration (mean ± standard deviation 2.73% ± 0.07%) was significantly larger than before atipamezole administration (1.95% ± 0.13%; p < 0.0001). CONCLUSION AND CLINICAL RELEVANCE: The role of α2-adrenoceptors in inhaled anesthetic-induced immobility may be larger than previously thought. Antagonism of an α2-adrenoceptor agonist during inhalation anesthesia may result in an increase in MAC disproportionate to the MAC reduction induced by the agonist.

Effects of dexmedetomidine, with or without vatinoxan (MK-467), on minimum alveolar concentration of isoflurane in cats.

OBJECTIVE: To characterize the effects of dexmedetomidine, with or without vatinoxan, on the minimum alveolar concentration of isoflurane (MACISO) in cats. STUDY DESIGN: Randomized crossover experimental study. ANIMALS: A group of six adult healthy male neutered cats. METHODS: Cats were anesthetized with isoflurane in oxygen and instrumented. Dexmedetomidine was administered using a target-controlled infusion system to achieve 10 target plasma concentrations ranging from 0 to 40 ng mL-1. Additionally, vatinoxan or an equivalent volume of saline was administered using a target-controlled infusion system to achieve a target plasma concentration of 4 µg mL-1. Pulse rate (PR), respiratory rate, systolic arterial pressure (SAP), hemoglobin oxygen saturation, body temperature, end-tidal partial pressure of carbon dioxide and drug concentrations were measured. MACISO was determined at each target plasma dexmedetomidine concentration using the bracketing method and the tail clamp technique. Pharmacodynamic models were fitted to the plasma dexmedetomidine concentration-MACISO. Pharmacodynamic parameters were tested for equivalence, and if rejected, for difference. RESULTS: Dexmedetomidine alone decreased MACISO in a plasma concentration-dependent manner. Maximum reduction was 77 ± 4%; the dexmedetomidine concentration producing 50% of the maximum decrease (IC50) was 0.77 ng mL-1. Vatinoxan increased MACISO in the absence of dexmedetomidine, decreased the potency of dexmedetomidine for its MACISO-reducing effect (IC50 = 12 ng mL-1) and lessened the maximum MACISO reduction (60 ± 14%). PR decreased less and SAP increased less when dexmedetomidine was administered with vatinoxan compared with saline. CONCLUSION AND CLINICAL RELEVANCE: Vatinoxan altered the effect of dexmedetomidine on MACISO. A high plasma dexmedetomidine concentration in the presence of vatinoxan resulted in a large decrease in MACISO, with attenuation of dexmedetomidine-induced cardiovascular effects. The vatinoxan-dexmedetomidine combination may provide clinical benefits in isoflurane-anesthetized cats.