Clinical Characteristics and Biotransformation of Sevoflurane in Healthy Human Volunteers

Abstract

Sevoflurane (fluoromethyl 2,2,2-trifluoro-1-[trifluoromethyl] ethyl ether) was submitted to phase-1 studies in man following extensive testing in animal species without evidence of toxicity. Sevoflurane, 2-3% inspired during maintenance, was administered with O2 to produce 1 h of anesthesia in 6 healthy adult male volunteers. Respiratory and cardiovascular functions, the EEG, arterial blood gases, blood sevoflurane, inorganic fluoride and total, nonvolatile fluorine concentrations and inspired and mixed expired sevoflurane concentrations were measured during exposure. Concentrations of expired sevoflurane, blood and urinary fluoride and total nonvolatile fluorine metabolites were measured after anesthesia. During exposure spontaneous respiratory frequency increased 28%, respiratory minute volume changed insignificantly, and PaCO2 [arterial partial pressure of CO2] averaged 50 torr. PaO2s remained near 400 torr. Arterial systolic blood pressure declined an average of 17%. Pulse rate changed insignificantly. After 1 h of exposure arterial blood serum inorganic fluoride concentrations averaged 22 .mu.M and plasma nonvolatile organic fluorine concentrations averaged 9.1 mg/l, or 61.3 .mu.M. Uptakes of sevoflurane averaged 94 (.+-. 63 SD) mmol. Following exposure 37 (.+-. 12) mmol of unaltered sevoflurane were estimated to be excreted in exhaled air and 0.90 mmol of inorganic fluoride and 163 mg, or 1.43 (.+-. 0.26) mmol, of organic fluorine were excreted in the urine. Recoveries in exhaled air and urine averaged 51.5 (.+-. 22.4) % of uptake. There was no significant drug-exposure-related change in the chest radiogram, ECG, EEG, urinalysis results, complete blood count, prothrombin time, serum electrolytes, transaminases or hepatic and renal functions during 4 wk following exposure compared with preexposure values. Sevoflurane produced anesthesia of excellent quality: it appears to undergo limited biotransformation and to have little or no systemic toxicity.