This study reports the pharmacokinetics of buprenorphine, following i.v. and buccal administration, and the relationship between buprenorphine concentration and its effect on thermal threshold. Buprenorphine (20 μg/kg) was administered intravenously or buccally to six cats. Thermal threshold was determined, and arterial blood sampled prior to, and at various times up to 24 h following drug administration. Plasma buprenorphine concentration was determined using liquid chromatography/mass spectrometry. Compartment models were fitted to the time-concentration data. Pharmacokinetic/pharmacodynamic models were fitted to the concentration-thermal threshold data. Thermal threshold was significantly higher than baseline 44 min after buccal administration, and 7, 24, and 104 min after i.v. administration. A two- and three-compartment model best fitted the data following buccal and i.v. administration, respectively. Following i.v. administration, mean ± SD volume of distribution at steady-state (L/kg), clearance (mL·min/kg), and terminal half-life (h) were 11.6 ± 8.5, 23.8 ± 3.5, and 9.8 ± 3.5. Following buccal administration, absorption half-life was 23.7 ± 9.1 min, and terminal half-life was 8.9 ± 4.9 h. An effect-compartment model with a simple effect maximum model best predicted the time-course of the effect of buprenorphine on thermal threshold. Median (range) ke0 and EC50 were 0.003 (0.002-0.018)/min and 0.599 (0.073-1.628) ng/mL (i.v.), and 0.017 (0.002-0.023)/min and 0.429 (0.144-0.556) ng/mL (buccal).

The aim of this study was to examine the effect of the sampling site on the drug concentration-time profile, following intravenous or buccal (often called 'oral transmucosal') drug administration. Buprenorphine (20 μg/kg) was administered IV or buccally to six cats. Blood samples were collected from the carotid artery and the jugular and medial saphenous veins for 24 h following buprenorphine administration. Buprenorphine concentration-time data were examined using noncompartmental analysis. Pharmacokinetic parameters were compared using the Wilcoxon signed rank test, applying the Bonferroni correction. Significance was set at P < 0.05. Following IV administration, no difference among the sampling sites was found. Following buccal administration, maximum concentration [jugular: 6.3 (2.9-9.8), carotid: 3.4 (1.9-4.9), medial saphenous: 2.5 (1.7-4.1) ng/mL], area under the curve [jugular: 395 (335-747), carotid: 278 (214-693), medial saphenous: 255 (188-608) ng·min/mL], and bioavailability [jugular: 47 (34-67), carotid: 32 (20-52), medial saphenous: 23 (16-55)%] were higher in the jugular vein than in the carotid artery and medial saphenous vein. Jugular venous blood sampling is not an acceptable substitute for arterial blood sampling following buccal drug administration.

Whole-blood propranolol concentrations were estimated for 12 hours after a single 80 mg oral dose was given in six patients taking cimetidine and two weeks after they had stopped the drug. Mean blood propranolol concentrations were higher throughout the sampling period when the patients were taking cimetidine than when they were not, and the difference was statistically significant between one and four hours (p <0 05). The mean relative bioavailability of propranolol, measured as the area under the concentration time curve, was significantly higher when the patients were taking cimetidine (p < 0 025). The mean increase in bioavailability was 136-5 4 57-6%, and the results were consistent in each subject.It is concluded from these results that cimetidine reduces the hepatic first-pass extraction of propranolol.

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The effects of 9 beta‐methyl carbacyclin, a chemically stable analogue of epoprostenol (prostacyclin, PGI2) were studied, in comparison with epoprostenol, both in vitro and in vivo in man. In vitro 9 beta‐methyl carbacyclin and epoprostenol inhibited platelet aggregation induced by ADP, collagen, the endoperoxide analogue U46619 and arachidonic acid. The potency of 9 beta‐methyl carbacyclin relative to epoprostenol was comparable in ADP and collagen‐aggregated platelet rich plasma (PRP), 9 beta‐methyl carbacyclin being 0.01 times as active as epoprostenol. The anti‐aggregatory potencies of the two compounds were comparable in PRP and whole blood. The phosphodiesterase inhibitor isobutyl methyl xanthine enhanced the anti‐aggregatory activity of both compounds in vitro. 9 beta‐methyl carbacyclin and epoprostenol elevated platelet cyclic AMP, 9 beta‐methyl carbacyclin being 0.04 times as active as epoprostenol. In a placebo controlled trial both drugs produces significant headache and facial flushing when compared with placebo. Nasal stuffiness, abdominal discomfort and nausea were reported on all three treatments. Both drugs caused significant and comparable increase in heart rate and decrease in pre‐ejection (PEP) and PEP/left ventricular ejection time (LVET) ratio compared with placebo. Systolic and diastolic blood pressure, LVET and QS2 index were unchanged. Platelet aggregation responses to ADP were significantly inhibited by all three doses of both drugs compared with placebo. Bleeding time was significantly longer during epoprostenol infusion than either placebo or 9 beta‐methyl carbacyclin infusion. Neither drug had significant effect, compared with placebo, on kaolin activated clotting time in PPP, PRP or in PRP in the presence of heparin, prothrombin time, partial thromboplastin time, thrombin clotting time, fibrinogen, fibrinogen degradation products or euglobulin clot lysis time. The pharmacodynamic effects and duration of action of 9 beta‐methyl carbacyclin and of epoprostenol are similar; 9 beta‐methyl carbacyclin is approximately 100 times less potent than epoprostenol in man.

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