Four tetracyclines were studied in dogs to determine the relation between their lipophilicity and various other pharmacological characteristics. Lipid solubility correlated inversely with the mean concentration of drug in arterial plasma and renal uptake and excretion, and directly with the biliary concentration gradient (level in bile/level of free drug in serum). Only the more lipophilic congeners minocycline and doxycycline passed the blood-brain and blood-ocular barriers in detectable concentrations. Mean levels of minocycline in the brain exceeded those of doxycycline by almost threefold; the difference was of borderline statistical significance (P = 0.05 to 0.1). Lipophilicity correlated inversely with the concentration of antibiotic in renal medulla but not in renal cortex or in the liver. When intestinal loops containing saline, milk, or 10% Gelusil were studied, the only combination exhibiting striking intraluminal accumulation was doxycycline in milk. These results indicate that lipophilicity correlates with many, but not all, of the transport characteristics of tetracycline antibiotics.Since the discovery of the tetracycline antibiotics over 25 years ago, a number of molecular modifications have been made with a view to improving tissue distribution, prolonging their half-life, augmenting intestinal absorption, and enhancing their antibacterial activity. Many of these objectives have been met in minocycline and doxycycline (6,9,10,25,26,34,41). Of additional interest is the fact that neither of these tetracyclines appears to require a major adjustment in dose in the presence of renal failure (6, 41), suggesting that they are extensively eliminated by nonrenal routes. Doxycycline has been demonstrated to be excreted extensively via the intestine (41). The data relative to minocycline, however, are inconclusive, and biliary excretion (29), intestinal excretion (6), and metabolic degradation (25) The purpose of the present investigation was to compare minocycline, doxycycline, tetracycline, and oxytetracycline with regard to their uptake and excretion by the liver and kidney, and their penetration into ileal contents, brain, cerebrospinal, and ocular fluids. The studies were carried out in a canine model that has been employed in previous investigations in our laboratory (5).MATERIALS AND METHODS Surgical preparation. The surgical preparation procedure has been described previously (5). Healthy mongrel dogs weighing 20 to 29 kg were anesthetized. Intravascular cannulas were placed in the femoral artery and vein and left renal, portal, and hepatic veins for aspiration of blood. Clotting was prevented by flushing the cannulas with heparin. Flow probes (Statham Co., Los Angeles, Calif.) were applied to the left renal and portal veins. Mean arterial pressure was recorded with a pressure transducer. Both ureters and the common bile duct were catheterized, and the cystic duct was ligated.Several additional procedures not performed in previous studies of this model were carried out. The terminal ileum was mobi...

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RECENT STUDIES have revealed that enflurane (Ethrane| or 1,12-trifluoro-2-ehlorethyl difluoromethyl ether is a potent anaesthetic in both animals and man. 1,~,3 Dobkin and his associates have reported that circulatory dynamics and cardiac rhythm remain relatively stable during enflurane anaesthesia in man, 1 but their findings are complicated by preanaesthetic medication, induction agents, muscle relaxants, surgical trauma, controlled respiration, and respiratory alkalosis. Accordingly, the present study was designed to obtain information on the haemodynamic effects of enflurane in man at constant carbon dioxide tension. METHODSTen male volunteers ranging in age from 21 to 35 years were interviewed and informed consent obtained. The procedures were approved by the Committee on Human Experimentation, Clinical Study Unit, Tufts University School of Medicine and New England Medical Center Hospitals. Each volunteer was admitted to the Clinical Study Unit three days prior to the study for complete history, physical examination, and laboratory tests, including electrocardiogram, chest X-ray, haematocrit, haemoglobin, creatinine, blood urea nitrogen, bilirubin, SGOT, SGPT and LDH, prothrombin time, alkaline phosphatase, sedimentation rate, and urine analysis. To prevent control of ventilation by positive pressure being a factor during the study, the volunteers were trained to use the ventilator. On the day following admission, they were instructed in the use of the Bennett anaesthesia ventilator. Tidal volume and frequency of respiration were set according to the Radford nomogram and the frequency was adjusted to achieve normal ad:erial pH and PaCO_,. The values obtained were noted.On the morning of the experiment, after fasting for at least nine hours, the trained volunteer was brought to the study room. The radial artery was cannulated. A venous catheter (#18 Sorensen) was inserted into the right ventricle through the right basilic vein for measurement of right ventricular end-diastolic pressure. Four surface EKC electrodes were applied. Needle electrodes were placed to obtain bipolar EEG tracings.