The effect of oxygen on propofol-induced inhibition of microsomal cytochrome P450 3A4.
We have shown previously that both hypoxia and propofol may inhibit the metabolism of midazolam. We now wished to see whether there was any additive or synergistic effect when they occurred together. Microsomes were incubated with 20 microns midazolam for 60 min, and propofol 0, 50, 100 or 1000 microM was added. Incubates were further subdivided so that the environment contained 0, 10, 21 or 70% oxygen. The results confirmed our earlier study showing that propofol only had a significant inhibitory effect at a concentration greater than that seen clinically (1000 microM). Anoxia was the only environment in which significant depression of the metabolism of midazolam occurred at all concentrations of propofol. This reduced it to almost zero. Post hoc analysis of the data showed that, with the greatest concentration of propofol (1000 microM), there was increasing inhibition of metabolism of midazolam with increases of oxygen from 10 to 70%.
Miller
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Addenbrooke's NHS Trust, Cambridge, UK.
Park
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GR
D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D014151:Anti-Anxiety Agents / Q000493:pharmacokinetics; D001711:Biotransformation; D015687:Cell Hypoxia / Q000502:physiology; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D008874:Midazolam / Q000493:pharmacokinetics; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D010100:Oxygen / Q000494:pharmacology*; D015742:Propofol / Q000494:pharmacology*
D018686:Anesthetics, Intravenous; D014151:Anti-Anxiety Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam; D010100:Oxygen; D015742:Propofol