caa a22 4500 475818075 CHVBK 20180406123814.0 cr unu---uuuuu 170329e20000301xx s 000 0 eng 10.1007/s002280050707 doi (NATIONALLICENCE)springer-10.1007/s002280050707 Human halothane metabolism, lipid peroxidation, and cytochromes P 4502A6 and P 4503A4 [Elektronische Daten] [E. D. Kharasch, D. C. Hankins, K. Fenstamaker, K. Cox] Objective: Halothane undergoes both oxidative and reductive metabolism by cytochrome P 450 (CYP), respectively causing rare immune-mediated hepatic necrosis and common, mild subclinical hepatic toxicity. Halothane also causes lipid peroxidation in rodents in vitro and in vivo, but in vivo effects in humans are unknown. In vitro investigations have identified a role for human CYPs 2E1 and 2A6 in oxidation and CYPs 2A6 and 3A4 in reduction. The mechanism-based CYP2E1 inhibitor disulfiram diminished human halothane oxidation in vivo. This investigation tested the hypotheses that halothane causes lipid peroxidation in humans in vivo, and that CYP2A6 or CYP3A4 inhibition can diminish halothane metabolism. Methods: Patients (n=9 each group) received single doses of the mechanism-based inhibitors troleandomycin (CYP3A4), methoxsalen (CYP2A6) or nothing (controls) before a standard halothane anaesthetic. Reductive halothane metabolites chlorotrifluoroethane and chlorodifluoroethylene in exhaled breath, fluoride in urine, and oxidative metabolites trifluoroacetic acid and bromide in urine were measured for 48 h postoperatively. Lipid peroxidation was assessed by plasma F2-isoprostane concentrations. Results: The halothane dose was similar in all groups. Methoxsalen decreased 0- to 8-h trifluoroacetic acid (23 ± 20 μmol vs 116 ± 78 μmol) and bromide (17 ± 11 μmol vs 53 ± 49 μmol) excretion (P < 0.05), but not thereafter. Plasma F2-isoprostanes in controls were increased from 8.5 ± 4.5 pg/ml to 12.5 ± 5.0 pg/ml postoperatively (P < 0.05). Neither methoxsalen nor troleandomycin diminished reductive halothane metabolite or F2-isoprostane concentrations. Conclusions: These results provide the first evidence for halothane-dependent lipid peroxidation in humans. Methoxsalen effects on halothane oxidation confirm in vitro results and suggest limited CYP2A6 participation in vivo. CYP2A6-mediated, like CYP2E1-mediated human halothane oxidation, can be inhibited in vivo by mechanism-based CYP inhibitors. In contrast, clinical halothane reduction and lipid peroxidation were not amenable to suppression by CYP inhibitors. Springer-Verlag Berlin Heidelberg, 2000 Key words Halothane nationallicence Lipid peroxidation nationallicence Hepatotoxicity nationallicence Kharasch E. D. Department of Anesthesiology, Box 356540, University of Washington, Seattle, WA 98195, USA e-mail: kharasch@u.washington.edu Tel.: +1-206-5432039; Fax: +1-206-6853079, US aut Hankins D. C. Department of Anesthesiology, Box 356540, University of Washington, Seattle, WA 98195, USA e-mail: kharasch@u.washington.edu Tel.: +1-206-5432039; Fax: +1-206-6853079, US aut Fenstamaker K. Department of Anesthesiology, Box 356540, University of Washington, Seattle, WA 98195, USA e-mail: kharasch@u.washington.edu Tel.: +1-206-5432039; Fax: +1-206-6853079, US aut Cox K. Department of Anesthesiology, Box 356540, University of Washington, Seattle, WA 98195, USA e-mail: kharasch@u.washington.edu Tel.: +1-206-5432039; Fax: +1-206-6853079, US aut https://doi.org/10.1007/s002280050707 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s002280050707 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Kharasch E. D. Department of Anesthesiology, Box 356540, University of Washington, Seattle, WA 98195, USA e-mail: kharasch@u.washington.edu Tel.: +1-206-5432039; Fax: +1-206-6853079, US aut NATIONALLICENCE 700 1- Hankins D. C. Department of Anesthesiology, Box 356540, University of Washington, Seattle, WA 98195, USA e-mail: kharasch@u.washington.edu Tel.: +1-206-5432039; Fax: +1-206-6853079, US aut NATIONALLICENCE 700 1- Fenstamaker K. Department of Anesthesiology, Box 356540, University of Washington, Seattle, WA 98195, USA e-mail: kharasch@u.washington.edu Tel.: +1-206-5432039; Fax: +1-206-6853079, US aut NATIONALLICENCE 700 1- Cox K. Department of Anesthesiology, Box 356540, University of Washington, Seattle, WA 98195, USA e-mail: kharasch@u.washington.edu Tel.: +1-206-5432039; Fax: +1-206-6853079, US aut Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer