Abstract
Objective: The analgesic effect of codeine depends on its O-demethylation to morphine via sparteine oxygenase (CYP2D6) in the liver and presumably also via this enzyme in the CNS. We studied the ability of quinidine, which is a potent inhibitor of CYP2D6, to penetrate the blood brain barrier and its pssible impact on codeine O-demethylation in CNS.
Methods: The study comprised 16 extensive and one poor metaboliser of sparteine, who underwent spinal anaesthesia for urinary tract surgery or examination. Eight patients were given an oral dose of 125 mg codeine and 9 patients (including the poor metaboliser) were given 200 mg quinidine 2 h before the same dose of codeine. Plasma and spinal fluid samples were collected 2 h after codeine intake.
Results: Free concentrations of quinidine were 11-times lower in cerebrospinal fluid than in plasma, and ranged from 9–15 nmol·l−1. Morphine concentrations were significantly lower in patients pre-treated with quinidine, both in plasma (median 1.45 nmol·l−1, range 0.74–1.95 nmol·l−1 vs 9.86 nmol·l−1, range 4.59–28.4 nmol·l−1) and in cerebrospinal fluid (0.23, 0.16–0.61 nmol·l−1 vs 3.63, 0.6–8.09 nmol·l−1). The morphine/codeine concentration ratio in plasma (3.07×10−3, 1.68–3.68×10−3 vs 19.87×10−3, 9.87–66.22×10−3) and in cerebrospinal fluid (0.83×10−3, 0.58–1.45×10−3 vs 7.19×10−3, 2.03–17.7×10−3) was also lower. The morphine/-codeine concentration ratios were significantly lower in cerebrospinal fluid both without and with quinidine, but the difference between the plasma and spinal fluid ratios was significantly smaller with quinidine than without (p=0.0002).
Conclusion: Quinidine penetrates the blood brain barrier poorly, but quinidine pre-treatment leads to pronounced lowering of the cerebrospinal fluid concentration of morphine after codeine intake. However, the O-demethylation of codeine in CNS may not be totally blocked by quinidine.
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References
Adler TK, Fujimoto JM, Way EL, Baker EM (1955) The metabolic fate of codeine in man. J Pharmacol Exp Ther 114:251–262
Agon P, Braeckman R, van Haver D, Denutte H, Goethals P, Donche H, Vermullen F, Deman J, Kaufman J.-M (1988) Drug distribution in dog brain studied by positron emission tomography. Biopharmaceut Drug Disp 9:567–577
Alván G, Bechtel P, Iselius L, Gundert-Remy U (1990) Hydroxylation polymorhisms of debrisoquine and mephenytoin in European populations. Eur J Clin Pharmacol 39:533–537
Bigger JT, Hoffman BF (1990) Antiarrhytmic drugs. In: Goodman Gilman A, Rall TW, Nies AS, Taylor P (eds) The pharmacological basis of therapeutics. 8th ed. Pergamon Press, New York, pp 840–873
Brinn R, Brøsen K, Gram LF, haghfelt T, Otton SV (1986) Sparteine oxidation is practically abolished in quinidine-treated patients. Br J Clin Pharmacol 22:194–197
Brøsen K, Otton SV, Gram LF (1985) Sparteine oxidation polymorphism in Denmark. Pharmacol Toxicol 60:312–314
Chen ZR, Somogyi AA, Bochner F (1988) Polymorphic O-demethylation of codeine. Lancet II:914–915
Chen ZR, Irvine RJ, Bochner F, Somogui AA (1990) Morphine formation from codeine in rat brain: possible mechanism of codeine analgesia. Life Sci 46:1067–1074
Dayer P, Desmeules J, Leemann T, Striberni R (1988) Bioactivation of the narcotic drug codeine in human livers is mediated by the polymorphic monooxygenase catalyzing debrisoquine 4-hydroxylation (cytochrome P450db1/bufI). Biochem Biophys Res Comm 152:411–416
Desmeules J, Gascon M-P, Dayer P, Magistris M (1991) Impact of environmental and genetic factors on codeine analgesia. Eur J Clin Pharmacol 41:23–26
Eichelbaum M, Gross AS (1990) The genetic polymorphism of debrisoquine/sparteine metabolism-clinical aspects. Pharmacol Ther 46:377–394
Fishman J, Hahn EF, Norton BI (1976) N-demethylation of morphine in rat brain is located in sites with high opiate receptor content. Nature 261:64–65
Gaedigk A, Blum M, Gaedigk R, Eichelbaum M, Meyer UA (1991) Deletion of the entire cytochrome P450 CYP2D6 gene as a cause of impaired drug metabolism in poor metabolizers of the debrisoquine/sparteine polymorphism. Am J Hum Genet 48:943–950
Hiatt EP, Quinn GP (1945) The distribution of quinine, quinidine, cinchonine and cinchonidine in fluids and tissues of dogs. J Pharmacol Exp Ther 83:101–105
Hofmann U, Fromm MF, Johnson S, Mikus G (1995) Simultaneous determination of dihydrocodeine and dihydromorphine in serum by gas chromatography/tandem mass spectrometry. J Chromatogr 663:59–65
Juan H (1977) Inhibition of algesic effect of bradykinin and acetylcholine by mepacrine. Naunyn-Schmiedeberg's Arch Pharmacology 301:23–27
Kagimoto M, Heim M, Kagimoto K, Zeugin T, Meyer UA (1990) Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolizers of debrisoquine. J Biol Chem 265:17209–17214
Mikus G, Bochner F, Eichelbaum M, Horak P, Somogyi AA, Spector S (1994) Endogenous codeine and morphine in poor and extensive metabolisers of the CYP2D6 (debrisoquine/sparteine) polymorphism. J Pharmacol Exp Ther 268:546–551
Nielsen F, Nielsen KK, Brøsen K (1994) Determination of quinidine, dihydroquinidine, (3s)-3-hydroxyquinidine, and quinidine-N-oxide in plasma and urine by high performance liquid chromatography. J Chromatogr 660:103–110
Nielsen MD, Brøsen K, Gram LF (1990) A dose-effect study of the in vivo inhibitory effect of quinidine on sparteine oxidation in man. Br J Clin Pharmacol 29:299–304
Niznik HB, Tyndale RF, Sallee FR, Gonzales FJ, Hardwick JP, Inaba T, Kalow W (1990) The dopamine transporter and cytochrome P450IID1 (debrisoquine-hydroxylase) in brain: resolution and identification of two distinct [3H]GBR-12935 binding proteins. Arch Biochem Biophys 276:424–432
Oldendorf WH, Hyman S, Braun L, Oldendorf SZ (1972) Blood brain barrier: penetration of morphine, codeine, heroin, and methadone after carotid injection. Science 128: 984–986
Otton SV, Inaba T, Kalow W (1984) Competitive inhibition of sparteine oxidation in human liver by beta-adrenoceptor antagonists and other cardiovascular drugs. Life Sci 34:73–80
Pasternak GW, Wood PJ (1986) Multiple mu opiate receptors. Life Sci 38:1889–1898
Sindrup SH, Brøsen K, Bjerring P, Arendt-Nielsen L, Angelo HR, Larsen U, Gram LF (1990) Codeine increases pain thresholds to copper vapor laser stimuli in extensive but not in poor metabolizers of sparteine. Clin Pharmacol Ther 48:686–693
Sindrup SH, Arendt-Nielsen L, Brøsen K, Bjerring P, Angelo HR, Eriksen B, Gram LF (1992) The effect of quinidine on the analgesic effect of codeine. Eur J Clin Pharmacol 42:587–592
Sindrup SH, Poulsen L, Brøsen K, Arendt-Nielsen L, Gram LF (1993) Are poor metabolisers of sparteine/debrisoquine less pain tolerant than extensive metabolisers. Pain 53:335–339
Tyndale RF, Sunahara R, Inaba T, Kalow W, Gonzales FJ, Niznik HB (1991) Neuronal cytochrome P450IID1 (debrisoquine/sparteine-type): potent inhibition of activation by (-)-cocaine and nucleotide sequence identity to human hepatic P450 gene CYP2D6. Mol Pharmacol 40:63–68
Yue QY, Svensson J-O, Alm C, Sjöqvist F, Säwe J (1989) Codeine O-demethylation co-segregates with polymorphic debrisoquine hydroxylation. Br J Clin Pharmacol 28:639–645
Zanger UM, Vilbois F, Hardwick J, Meyer UA (1988) Absence of hepatic cytochrome P450bufI causes genetically deficient debrisoquine oxidation in man. Biochemistry 27:5447–5454
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Sindrup, S.H., Brøsen, K., Nielsen, F. et al. Impact of quinidine on plasma and cerebrospinal fluid concentrations of codeine and morphine after codeine intake. Eur J Clin Pharmacol 49, 503–509 (1996). https://doi.org/10.1007/BF00195938
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DOI: https://doi.org/10.1007/BF00195938