The Impact of MK-467 on Certain Pharmacokinetic and Pharmacodynamic Properties of Selected Drugs Affecting the Central Nervous System in Dogs

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http://urn.fi/URN:ISBN:978-951-51-3510-0
Title: The Impact of MK-467 on Certain Pharmacokinetic and Pharmacodynamic Properties of Selected Drugs Affecting the Central Nervous System in Dogs
Author: Bennett, Rachel
Contributor: University of Helsinki, Faculty of Veterinary Sciences
Thesis level: Doctoral dissertation (article-based)
Abstract: Background and rationale Alpha2-adrenoceptor agonists, such as medetomidine, are commonly used in veterinary medicine for the sedation and premedication of animals. Their use is associated with a range of undesirable pharmacodynamic effects most notably vasoconstriction, bradycardia (Pypendop and Verstegen 1998), hyperglycaemia (Hsu and Hummel 1981) and diuresis (Thurmon et al. 1978). MK-467 is a peripheral α2-adrenoceptor antagonist (Clineschmidt et al. 1988), which ameliorates the aforementioned side effects of (dex-)medetomidine whilst maintaining the sedative effects (Enouri et al. 2006; Honkavaara et al. 2008; Restitutti et al. 2012; Rolfe et al. 2012). Therefore MK-467 may offer some important clinical benefits, although some questions remain concerning its pharmacodynamic and pharmacokinetic interaction with other anaesthetic drugs. The main objectives of the following studies were to: determine the protein-binding fraction of MK-467, to assess the possible role of MK-467 as a P-glycoprotein substrate in vitro; and to evaluate the impact of MK-467 on the disposition of medetomidine in vivo. During in vivo studies, the impact of MK-467 on the centrally mediated effects: sedation and antinociception and peripherally mediated cardiovascular effects of medetomidine were assessed simultaneously. The protein-binding characteristics of MK-467 were investigated using the technique of equilibrium dialysis. Drug concentrations were measured using the technique of liquid chromatography and tandem mass spectrometry. Protein-binding fraction of MK-467 was approximately 70% and it was unaltered by the presence of medetomidine. Transcellular drug movement was determined using Madin-Darby Canine Kidney cells - wild type (WT-MDCKII) and cells transfected with the human gene encoding P-glycoprotein (MDR1-MDCKII). In addition to MK-467, acepromazine, a putative P-glycoprotein substrate, and dexmedetomidine were also investigated. Based on measured drug concentrations, apparent permeability of the cells was calculated and used to determine the role of active transport in the transcellular movement of the selected drugs. Passive movement of MK-467 was undetectable. Therefore, efflux ratios for MK-467 were not determined. However, movement in the basolateral to apical direction occurred in both cell lines. The identity of the possible transporter remains unclear. Transport ratios for acepromazine were 1.17:1:1.0 and 1.51:1.0 for WT-MDCKII and MDR1-MDCKII transfected cells, respectively. Currently acepromazine cannot be defined as a P-glycoprotein substrate based on these results. Whilst, dexmedetomidine transport ratios were 0.98:1.0 and 1.15:1.0 for WT-MDCKII and MDR1-MDCKII respectively. It does not appear to be a substrate for an active transport mechanism. In vivo drug concentration data underwent non-compartmental analysis. MK-467 increased the volume of distribution and clearance of dexmedetomidine and levomedetomidine, whilst area under the curve and elimination half-life were significantly decreased when compared with medetomidine alone. Medetomidine significantly decreased the clearance of alfaxalone during co-administration, whilst the additional administration of MK-467 counteracted the effect of medetomidine on alfaxalone clearance. The quality and duration of sedation were assessed using a composite sedation score, whilst hypnosis was evaluated by measurement of bispectral index or analysis of the electroencephalogram. Antinociception was determined by the measurement of limb withdrawal times and head lift times following the application of a nociceptive stimulus applied to the nailbed of a hind limb digit. Measured haemodynamic variables included arterial blood pressure, heart rate, cardiac output and systemic vascular resistance. Ventilatory effects of medetomidine and co-administered MK-467 were also assessed by the analysis of arterial and venous blood gas samples taken during these studies. The co-administration of MK-467 did not alter the initial quality of sedation but reduced the duration of sedation produced by medetomidine. MK-467 significantly diminished the antinociceptive action of medetomidine. MK-467 ameliorated the cardiovascular, haemodynamic and ventilatory effects of medetomidine prior to and during general anaesthesia. In conclusion, MK-467 is moderately protein bound and it is unlikely to be subject to drug-drug interactions in vivo. MK-467 shows little passive movement in MDCKII cells but may undergo active cellular efflux. It is unclear whether MK-467 is suitable for use in animals carrying the P-glycoprotein mutation. The addition of MK-467 alters the disposition of co-administered drugs resulting in lower plasma drug concentrations. The reduction in some pharmacodynamic effects may be attributed to the alteration in pharmacokinetics caused by the peripheral α2-adrenoceptor antagonist.Miss Bennett’s PhD research investigated the effect of MK-467, a peripherally acting (i.e. having an effect outside the brain) α2-adrenoceptor antagonist on some of the pharmacodynamic effects and pharmacokinetic properties of the α2-adrenoceptor agonist medetomidine and the injectable anaesthetic, alfaxalone. Medetomidine commonly used in small animal clinical practice for its profound sedative and analgesia effects, which result from an action within the brain and spinal cord. Miss Bennett’s PhD studies consisted of both in vitro and in vivo studies. The main objectives of the studies were to: determine the protein-binding fraction of MK-467, to assess the possible role of MK-467 as a P-glycoprotein substrate in vitro; and to evaluate the impact of MK-467 on the disposition of medetomidine and alfaxalone in vivo. During in vivo studies, the impact of MK-467 on the centrally mediated effects (i.e. effects occurring within the brain or spinal cord): sedation and antinociception and peripherally mediated cardiovascular effects of medetomidine were assessed simultaneously. The protein-binding characteristics of MK-467 were investigated alone and in the presence of medetomidine. Protein-binding fraction of MK-467 was approximately 70% and it was unaltered by the presence of medetomidine. This is important since alterations in protein binding may lead to enhanced pharmacodynamic effects of MK-467 and other co-administered drugs. Miss Bennett investigated the possible role of MK-467 as a substrate for the efflux transporter P-glycoprotein using an in vitro technique. This study used wild type cells and those transfected with the human gene encoding P-glycoprotein. Based on measured drug concentrations, apparent permeability of the cells was calculated and used to determine the role of active transport in the transcellular movement of the MK-467. Passive movement of MK-467 was undetectable. Therefore, efflux ratios for MK-467 were not determined. However, movement in the basolateral to apical direction occurred in both cell lines suggesting that a transporter may be involved in drug movement out of the cells. The identity of the transporter remains unclear. Following pharmacokinetic analysis of in vivo data, Miss Bennett found that MK-467 increased the volume of distribution and clearance of dexmedetomidine and levomedetomidine (the enantiomers of medetomidine), whilst MK-467 significantly decreased the elimination half-life of the said enantiomers when compared with medetomidine alone. During co-administration, medetomidine significantly decreased the clearance of alfaxalone, whilst the additional administration of MK-467 counteracted the effect of medetomidine on alfaxalone clearance. The quality and duration of sedation were assessed using a composite sedation score (higher scores indicate greater sedation), whilst hypnosis was evaluated by measurement of bispectral index or analysis of the electroencephalogram (i.e. electrical activity within the brain). Analgesia was determined by the measurement of time taken for animals to withdraw their limb and lift their head following the application of a nociceptive stimulus applied to a hind limb digit. The longer the time between application and response indicating an greater analgesic effect. Ventilatory effects of medetomidine and co-administered MK-467 were assessed by the analysis of arterial and venous blood gas samples taken during the studies. Whilst, measured haemodynamic variables included arterial blood pressure, heart rate, cardiac output and systemic vascular resistance. The co-administration of MK-467 did not alter the initial quality of sedation but reduced the duration of sedation produced by medetomidine. MK-467 significantly diminished the analgesic action of medetomidine. MK-467 ameliorated the cardiovascular, haemodynamic and ventilatory effects of medetomidine prior to and during general anaesthesia. In conclusion, MK-467 is moderately protein bound and it is unlikely to be subject to drug-drug interactions in vivo. MK-467 may undergo active cellular efflux. It remains unclear whether MK-467 is suitable for use in animals carrying the P-glycoprotein mutation. The addition of MK-467 alters the disposition of co-administered drugs resulting in lower plasma drug concentrations. The reduction in some pharmacodynamic effects may be attributed to the alteration in pharmacokinetics caused by the peripheral α2-adrenoceptor antagonist. This important in determining the required dose of medetomidine to achieve sedation and analgesia in the presence of MK-467.
URI: URN:ISBN:978-951-51-3510-0
http://hdl.handle.net/10138/195062
Date: 2017-06-30
Subject:
Rights: This publication is copyrighted. You may download, display and print it for Your own personal use. Commercial use is prohibited.


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