Herbal monoterpene alcohols inhibit propofol metabolism and prolong anesthesia time.
2,6-Diisopropylphenol (Propofol) is a short-acting intravenous anesthetic that is rapidly metabolized by glucuronidation and ring hydroxylation catalyzed by cytochrome P450. The goal of this research was to determine whether dietary monoterpene alcohols (MAs) could be used to prolong the anesthetic effect of propofol by inhibiting propofol metabolism in animals. Mice were injected intraperitoneally (i.p.) with MAs (100-200) mg/kg followed by the administration of 100 mg/kg propofol 40 min later via an i.p. injection. The time of the anesthesia of each mouse was recorded. It was found that (+/-)-borneol, (-)-carveol, trans-sobrerol, and menthol significantly extended the anesthetic effect of propofol (>3 times). The concentration of propofol in the mouse blood over time (up to 180 min) also increased in mice pre-treated with (-)-borneol, (-)-carveol, and trans-sobrerol. The volume of distribution of propofol decreased in the (-)-borneol (p<0.05), pre-treated group as compared to the propofol control group. Moreover, the maximum blood concentration of propofol and the concentration of propofol in the blood as indicated by the area under the curve were significantly increased in (-)-borneol and (-)-carveol pre-treated groups. Additional evidence using rat hepatocytes showed that (-)-borneol inhibited propofol glucuronidation whereas trans-sobrerol and (-)-carveol inhibited cytochrome P450 dependent microsomal aminopyrine N-demethylation. These results suggest that (-)-borneol extends propofol-induced anesthesia by inhibiting its glucuronidation in the mouse whereas trans-sobrerol (-)-carveol extends propofol-induced anesthesia by inhibiting P450 catalyzed propofol metabolism.
Li Lin
Alison
A
Pharmaceutical Sciences Department, University of Toronto, 19 Russell Street, Toronto, Ontario, M5S 2S2, Canada.
Shangari
Nandita
N
Chan
Tom S
TS
Remirez
Diadelas
D
O'Brien
Peter J
PJ
D000438:Alcohols / Q000494:pharmacology*; D000633:Aminopyrine N-Demethylase / Q000378:metabolism; D000758:Anesthesia; D018686:Anesthetics, Intravenous / Q000493:pharmacokinetics*; D000818:Animals; D001892:Camphanes / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D000081005:Cyclohexane Monoterpenes; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D020719:Glucuronides / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D039821:Monoterpenes / Q000494:pharmacology*; D015742:Propofol / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013729:Terpenes / Q000494:pharmacology
D000438:Alcohols; D018686:Anesthetics, Intravenous; D001892:Camphanes; D000081005:Cyclohexane Monoterpenes; D020719:Glucuronides; D039821:Monoterpenes; D013729:Terpenes; D003577:Cytochrome P-450 Enzyme System; C075856:carveol; C003316:sobrerol; D000633:Aminopyrine N-Demethylase; C022871:isoborneol; D015742:Propofol