Concomitant use of medetomidine and vatinoxan in laboratory and client-owned dogs : effects on drug absorption and disposition

α2-Adrenoceptor agonist drugs, such as medetomidine, are widely used in veterinary medicine for their sedative and analgesic effects. However, α2-adrenoceptor agonists have undesirable cardiovascular effects, most notably vasoconstriction and bradycardia. In view of this, vatinoxan (previously known as MK-467 and L-659’066) a peripherally acting α2-adrenoceptor antagonist has been investigated. Vatinoxan attenuates the negative cardiovascular effects of medetomidine in dogs while maintaining the sedative effects of the α2-adrenoceptor agonist. This thesis evaluated the effects of vatinoxan on the absorption and disposition of medetomidine and other selected drugs in laboratory and client-owned dogs following intramuscular administration; when the drugs were combined in the same syringe. The hypothesis was that vatinoxan would affect the plasma concentrations of concomitantly administered drugs, probably due to changes in tonus of the vasculature at the injection site. Furthermore, the distribution of vatinoxan and medetomidine into the central nervous system (CNS) was investigated. It was hypothesized that in dogs, vatinoxan would minimally enter the CNS, whereas the enantiomers of medetomidine would concentrate there. A group of six laboratory beagles participated in the preclinical studies, and 57 client-owned dogs were recruited into the clinical study. A randomized, clinical study was designed to investigate whether vatinoxan attenuates the bradycardic impact of medetomidine in client-owned dogs given medetomidine-butorphanol intramuscularly for minor diagnostic procedures. All analyses of drug concentrations were performed with liquid chromatography tandem mass spectrometry. Heart rates were monitored by auscultation and sedation was scored. Also, the degree of sedation was determined. It was hypothesized that vatinoxan would alleviate bradycardia without reducing the intensity of clinical sedation. Vatinoxan initially increased plasma concentrations of concomitantly administered drugs. Improved cardiovascular performance in α2-adrenoceptor agonist-medicated dogs probably affected the absorption via improved blood flow in the muscle. Furthermore, the distribution of enantiomers of medetomidine into the CNS appeared to be high whereas only about 2% of the vatinoxan plasma concentration was detected in the CNS. Vatinoxan ameliorated medetomidine-induced bradycardia, but adequate clinical sedation with a faster onset and shorter duration was achieved. In conclusion, the increased absorption of concomitantly administered drugs by vatinoxan resulted in a quicker onset and shortened duration of the sedation. When vatinoxan was combined with medetomidine and butorphanol, it alleviated bradycardia and provided reliable sedation in healthy client-owned dogs. Rauhoittavien vaikutustensa vuoksi eläinlääketieteessä käytössä olevan lääkeryhmän α2-adrenoseptoriagonistien käyttöä rajoittaa tähän lääkeryhmään liittyvät verenkiertoelimistön haitalliset vaikutukset, kuten verisuonten supistuminen sekä alhainen sydämen syke. Tämän vuoksi pääosin keskushermoston ulkopuolella vaikuttava vastavaikuttaja, α2-adrenoseptoriantagonisti vatinoksaani (joka on aikaisemmin tunnettu myös nimillä MK-467 sekä L659,066) on ollut tutkimusten kohteena. Vatinoksaanin on osoitettu koirilla lievittävän α2-adrenoseptoriagonistien negatiivisia verenkiertoelimistöön kohdistuvia vaikutuksia säilyttäen niiden aiheuttaman sedaation. Vatinoksaanin aiheuttamat muutokset muiden lääkeaineiden plasmapitoisuuksissa voivat olla kliinisesti merkityksellisiä, koska ne voivat vaikuttaa sekä sedaation syvyyteen että kestoon: kun koira saa vatinoksaania lihaksensisäisesti, se sedatoituu nopeammin, mutta sedaation kesto lyhenee. Tämä selittyy vatinoksaanin aiheuttamilla muutoksiin lääkeaineiden imeytymisessä: kun lääkkeet imeytyvät nopeammin, sedaatio saavutetaan aikaisemmin, mutta toisaalta myös lääkeaineen poistuminen elimistöstä nopeutuu.