caa a22 4500 477057969 CHVBK 20180405111352.0 cr unu---uuuuu 170330e19960301xx s 000 0 eng 10.1007/BF00195938 doi (NATIONALLICENCE)springer-10.1007/BF00195938 Impact of quinidine on plasma and cerebrospinal fluid concentrations of codeine and morphine after codeine intake [Elektronische Daten] [S. Sindrup, K. Brøsen, F. Nielsen, U. Hofmann, G. Mikus, J. Asmussen, S. Ingwersen, C. Christensen] 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. Springer-Verlag, 1996 CYP2D6 nationallicence Quinidine nationallicence Codeine nationallicence morphine nationallicence plasma nationallicence cerebrospinal fluid nationallicence Sindrup S. Department of Clinical Pharmacology, Institute of Medical Biology, Odense University, DK-5000, Odense C, Odense, Denmark aut Brøsen K. Department of Clinical Pharmacology, Institute of Medical Biology, Odense University, DK-5000, Odense C, Odense, Denmark aut Nielsen F. Department of Clinical Pharmacology, Institute of Medical Biology, Odense University, DK-5000, Odense C, Odense, Denmark aut Hofmann U. Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany aut Mikus G. Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany aut Asmussen J. Department of Anesthesiology, Odense University Hospital, Odense, Denmark aut Ingwersen S. Pharmacokinetics, Pharmaceutical Division, Novo Nordisk A/S, M»løv, Denmark aut Christensen C. Institute of Pharmacology, Copenhagen University, Copenhagen, Denmark aut European Journal of Clinical Pharmacology Springer-Verlag 49/6(1996-03-01), 503-509 0031-6970 49:6<503 1996 49 228 https://doi.org/10.1007/BF00195938 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/BF00195938 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Sindrup S. Department of Clinical Pharmacology, Institute of Medical Biology, Odense University, DK-5000, Odense C, Odense, Denmark aut NATIONALLICENCE 700 1- Brøsen K. Department of Clinical Pharmacology, Institute of Medical Biology, Odense University, DK-5000, Odense C, Odense, Denmark aut NATIONALLICENCE 700 1- Nielsen F. Department of Clinical Pharmacology, Institute of Medical Biology, Odense University, DK-5000, Odense C, Odense, Denmark aut NATIONALLICENCE 700 1- Hofmann U. Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany aut NATIONALLICENCE 700 1- Mikus G. Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany aut NATIONALLICENCE 700 1- Asmussen J. Department of Anesthesiology, Odense University Hospital, Odense, Denmark aut NATIONALLICENCE 700 1- Ingwersen S. Pharmacokinetics, Pharmaceutical Division, Novo Nordisk A/S, M»løv, Denmark aut NATIONALLICENCE 700 1- Christensen C. Institute of Pharmacology, Copenhagen University, Copenhagen, Denmark aut NATIONALLICENCE 773 0- European Journal of Clinical Pharmacology Springer-Verlag 49/6(1996-03-01), 503-509 0031-6970 49:6<503 1996 49 228 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer