The specific aims of the research protocol are six-fold: 1. To test commonly used drugs for their ability to alter anesthetic metabolism and toxicity. Hepatic microsomes from male Fischer 344 (F 344) rats treated with B-blockers (propanolol, atenolol and timololol), calcium channel blockers (nifedipine, verapamil) and antithyroid drugs (methimazole and carbimazole) will be tested. Acute interactions with local anesthetics (lidocaine, bupivacaine,) and narcotics (fentanyl, sufentanil, alfentanil and carfentanil) will be studied in microsomes from untreated F344 rats. 2. To define the rat model of obesity and to examine the effect of obesity on anesthetic disposition, metabolism, and nephrotoxicity. F 344 rats made obese with high-fat diet will be compared to non-obese control rats. Partition coefficients for blood, liver, and microsomes will be determined for halothane (HAL), isoflurane (ISO) and enflurane (ENF). Liver and kidney blood flow in the presence and absence of anesthetics will be measured with radioactive microspheres. MAC and anesthetic and anesthetic metabolite blood levels will be determined. 3. To determine the combined effects of obesity and chronic renal insufficiency (CRI) on anesthetic metabolism and renal function. CRI will be surgically induced in F 344 rats fed one month on high fat chow. Obese rats will receive either HAL, ISO or ENF. 4. To determine the effects of obesity on ENF and ISO metabolism and renal function in humans. Obese patients will receive either ENF or ISO anesthesia. F- kinetics and renal function will be evaluated. Data from this study should help us to determine if patients are at risk and, thus to prevent anesthetic-induced toxicities. 5. To determine the effect of thyroid hormone levels on anesthetic metabolism and nephrotoxicity. Partition coefficients for blood, liver and microsomes; MAC; in vitro and in vivo rates of anesthetic defluorination; and renal function will be evaluated in triiodothyronine-induced hyperthyroid and surgically-induced hypothyroid rats. 6. To determine the relative contributions of kidney and lung as compared to liver in anesthetic metabolism. Microsomes from F 344 rats will be prepared and evaluated. The objective of our studies is to identify interactions of inhaled anesthetics with drugs and chemicals that would result in nephrotoxicity. Ultimately, identification of these toxic interactions should prevent toxicity in the human clinical setting.
