{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T02:16:19Z","timestamp":1777428979192,"version":"3.51.4"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2005,3,1]],"date-time":"2005-03-01T00:00:00Z","timestamp":1109635200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2005,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Pathology related alterations in the pharmacokinetics or the pharmacodynamics of propofol could contribute to the observed large variability in the hypnotic dose. We have tested the influence of diabetes mellitus on the induction dose and the pharmacokinetics and pharmacodynamics of propofol in rats. Diabetes was induced in rats by administration of streptozotocin (60 mg kg\u22121, i.p.) while control rats received vehicle intraperitoneally. All animals had glucose, cholesterol, triglycerides and albumin levels measured. In-vitro protein binding was determined by ultrafiltration. Rats were randomly split into set 1 (dose-concentration-effect study) with control and streptozotocin rats, and set 2 (pharmacokinetic study), with control and streptozotocin rats. Rats in the effect set received either a variable infusion of 6 mg kg\u22121 min\u22121 propofol until onset (induction dose) of the hypnotic effect (loss of the righting reflex), or a 15 mg kg\u22121 bolus to assess offset time (recovery of the righting reflex). Blood (Cblood) and brain (Cbrain) propofol concentrations at onset and offset were assayed by HPLC. In the pharmacokinetic study, propofol was administered intravenously at 6 mg kg\u22121 min\u22121 for 2 min. Arterial blood samples were collected between 0.5 and 540 min and assayed for propofol. A mixed effects compartmental pharmacokinetic modelling method (NONMEM) was used to analyse the observations and variabilities. The dose necessary for onset differed between streptozotocin and controls, and so did the pharmacokinetics with two- and three-compartment descriptions, respectively. Cblood and Cbrain at onset and offset were similar, possibly rejecting changes in pharmacodynamics. The total and unbound volume of distribution was significantly lower in the streptozotocin group with no differences in clearance (CL) between streptozotocin and controls, (mean (inter-animal CV%)) CL = 0.026 (17%) and 0.025 (62%) L min\u22121, respectively. Individual Bayes Vdss (volume of distribution at steady state) were different, (mean (s.d.)) Vdss = 7.7 (2.67) and 1.11 (0.09) L, respectively. The pharmacokinetic model was validated by comparison with the data from set 1. Simulations of total and unbound Cblood, for both groups, at the hypnotic dose for the controls, revealed differences throughout the time course of the pharmacokinetics. The difference observed in the induction dose of propofol to streptozotocin and control rats was due to alterations in the pharmacokinetics, secondary to the pathology.<\/jats:p>","DOI":"10.1211\/0022357055498","type":"journal-article","created":{"date-parts":[[2005,3,1]],"date-time":"2005-03-01T23:27:29Z","timestamp":1109719649000},"page":"317-325","source":"Crossref","is-referenced-by-count":13,"title":["Altered dose-to-effect of propofol due to pharmacokinetics in rats with experimental diabetes mellitus"],"prefix":"10.1093","volume":"57","author":[{"given":"N","family":"Leal","sequence":"first","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of the Basque Country , 48940 Leioa,","place":["Spain"]},{"name":"Dynakin Ltd , Abando, Vizcaya,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R","family":"Calvo","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of the Basque Country , 48940 Leioa,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"F Z","family":"Agrad","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of the Basque Country , 48940 Leioa,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J C","family":"Lukas","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of the Basque Country , 48940 Leioa,","place":["Spain"]},{"name":"Department of Pharmacy, Laboratory of Biopharmaceutics and Pharmacokinetics, University of Athens , Athens,","place":["Greece"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L","family":"de la Fuente","sequence":"additional","affiliation":[{"name":"PharmaDatum Ltd, Edificio BEAZ , Sangroniz, Sondika,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"E","family":"Suarez","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of the Basque Country , 48940 Leioa,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2005,3,1]]},"reference":[{"key":"2024103109412707200_cit1","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1213\/00000539-200103000-00020","article-title":"The determinants of propofol induction of anesthesia dose","volume":"92","author":"Adachi","year":"2001","journal-title":"Anesth. 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