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Correspondence |
* Sagamihara, Japan
Machida, Japan
To the Editor:
We previously reported that magnesium sulfate (MgSO4) increased the threshold of bupivacaine-induced seizures in rats.1 Since it is not clear that the pharmacokinetic interaction of bupivacaine with concomitant MgSO4 involves the mechanism of the inhibitory effect of MgSO4 on seizure, we planned the following study, using awake rats.
Eleven Sprague-Dawley rats were chronically catheterized and divided into two groups; five in Group M received an iv bolus dose (50 mg•kg-1) of MgSO4 over two minutes, followed by an infusion of 4 mg•kg-1•min-1 throughout the experiment. Six in Group S received an equal volume of normal saline. After two hours of the pretreatment with either solution, a bupivacaine bolus of 1 mg•kg-1 was administered intravenously, followed by an infusion of 0.4 mg•kg-1•min-1 for 15 min. Serial arterial samples were obtained after the bupivacaine infusion to measure the concentrations of magnesium, bupivacaine and its major metabolite, 3'-hydroxybupivacaine (3'-OH-Bup). We also measured those concentrations in the liver at the end of the study. The concentration-time profile during and following the bupivacaine administration was fitted to a two-compartment model, using ADAPT II.2 The estimated intercepts and slopes were used for the calculation of standard pharmacokinetic variables. Comparison was performed separately, using a t test (P < 0.05).
Serum magnesium concentrations and the pharmacokinetic variables are shown in the Table (available as additional material at www.cja-jca.org). In three rats of Group M, 3'-OH-Bup was detected over 60 min after the end of bupivacaine infusion, (range 17 to 58 ng•mL-1), while no 3'-OH-Bup was detected in Group S. The mean ± SD liver concentration of 3'-OH-Bup in Group M was 0.65 ± 0.14 µg•g-1 (wet weight). In four rats of Group S, this value was 0.31 ± 0.30 µg•g-1 (wet weight). In two rats of Group S, 3'-OH-Bup was not detected.
From these results, it is suggested that MgSO4 might activate bupivacaine hydroxylation by cytochrome P450 (CYP) in rat liver. It is known that some oxidations catalyzed by some CYPs are sensitive to magnesium. For instance, magnesium was shown to stimulate amitriptyline, carbamazepine or diazepam metabolism catalyzed by recombinant CYP3A4 and human liver microsomes.3,4 However, it had a strong inhibition effect on midazolam metabolism,5 indicating that the effect of magnesium on metabolism of CYP substrates is different. Taken together with the fact that CYP3A is the most abundant human CYP and that the major metabolites of bupivacaine are catalyzed by CYP3A, the administration of MgSO4 to obstetric patients could alter bupivacaine pharmacokinetics, resulting in a more rapid elimination of bupivacaine.
References
1 Okutomi T, Zhang Y, Cooper TB, Morishima HO. The effect of MgSO4 on bupivacaine-induced convulsions in nonpregnant and pregnant rats. Anesth Analg 2001; 92: S220.
2 D’Argenio DZ, Schumitzky A. A program package for simulation and parameter estimation in pharmacokinetic systems. Comput Programs Biomed 1979; 9: 115–34.[Medline]
3 Ueng YF, Kuwabara T, Chun YJ, Guengerich FP. Cooperativity in oxidations catalyzed by cytochrome P450 3A4. Biochemistry 1997; 36: 370–81.[Medline]
4 Yamazaki H, Ueng YF, Shimada T, Guengerich FP. Roles of divalent metal ions in oxidations catalyzed by recombinant cytochrome P450 3A4 and replacement of NADPH--cytochrome P450 reductase with other flavoproteins, ferredoxin, and oxygen surrogates. Biochemistry 1995; 34: 8380–9.[Medline]
5 Maenpaa J, Hall SD, Ring BJ, Strom SC, Wrighton SA. Human cytochrome P450 3A (CYP3A) mediated midazolam metabolism: the effect of assay conditions and regioselective stimulation by alpha-naphthoflavone, terfenadine and testosterone. Pharmacogenetics 1998; 8: 137–55.[Medline]
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