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 possible 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 x 10 (-3), 1.68-3.68 x 10 (-3) vs 19.87 x 10 (-3), 9.87-66.22 x 10 (-3) and in cerebrospinal fluid (0.83 d 10 (-3), 0.58-1.45 x 10 (-3) vs 7.19 x 10 (-3), 2.03-17.7 x 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 ratio 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.
Subject(s)
Analgesics, Opioid/blood , Codeine/blood , Cytochrome P-450 Enzyme System/metabolism , Mixed Function Oxygenases/metabolism , Morphine/blood , Quinidine/pharmacology , Administration, Oral , Adult , Aged , Analgesics, Opioid/administration & dosage , Analgesics, Opioid/cerebrospinal fluid , Analgesics, Opioid/pharmacokinetics , Blood-Brain Barrier , Central Nervous System/drug effects , Central Nervous System/enzymology , Codeine/administration & dosage , Codeine/cerebrospinal fluid , Codeine/pharmacokinetics , Cytochrome P-450 CYP2D6 , Cytochrome P-450 Enzyme Inhibitors , Dose-Response Relationship, Drug , Female , Gas Chromatography-Mass Spectrometry , Humans , Liver/drug effects , Liver/enzymology , Male , Methylation , Middle Aged , Mixed Function Oxygenases/antagonists & inhibitors , Morphine/administration & dosage , Morphine/cerebrospinal fluid , Quinidine/administration & dosage , Quinidine/pharmacokinetics , Sparteine/metabolismABSTRACT
An isocratic high-performance liquid chromatographic method has been developed for the determination of morphine, morphine-3-glucuronide, morphine-6-glucuronide and codeine in plasma, urine and cerebrospinal fluid. The use of an efficient solid-phase extraction procedure together with a forward optical scanning detector allows a detection limit of 500 pg/ml. The method was evaluated by examination of biological samples taken from newborn infants following the intravenous administration of morphine sulfate.
Subject(s)
Chromatography, High Pressure Liquid/methods , Codeine/blood , Codeine/cerebrospinal fluid , Codeine/urine , Morphine Derivatives/blood , Morphine Derivatives/cerebrospinal fluid , Morphine Derivatives/urine , Morphine/blood , Morphine/cerebrospinal fluid , Morphine/urine , Humans , Infant, Newborn , Injections, Intravenous , Morphine/administration & dosage , Reproducibility of ResultsABSTRACT
A method for the fast analysis of morphine (M), normorphine (NM), morphine-3- and -6-glucuronides (M3G and M6G) and codeine (C) is described which has the advantages of sensitivity, speed and specificity. Dihydrocodeine and heroin can also be assayed. The method is based on extraction of the opiates from serum, plasma and cerebrospinal fluid using reversed-phase solid-phase extraction columns, followed by reversed-phase high-performance liquid chromatography with native fluorescence detection. The extraction step provides greater than 95% recovery, and the response of the detection system is linear from 0.5 to beyond 750 ng. The method allows analysis of M, NM, M3G, M6G and C. No other drugs have been found to interfere with the assay. The assay offers a quick, cheap and reliable method of specifically determining morphine and its metabolites, including the potent M6G, from a small sample volume; this will be of advantage to both clinician and basic scientist.
Subject(s)
Chromatography, High Pressure Liquid , Morphine/analysis , Codeine/blood , Codeine/cerebrospinal fluid , Fluorescence , Humans , Microchemistry , Morphine/blood , Morphine/cerebrospinal fluid , Morphine Derivatives/blood , Morphine Derivatives/cerebrospinal fluid , Quality ControlABSTRACT
We have examined cerebrospinal fluid (CSF) from twelve patients who were not on any medication and found them to contain both morphine and codeine in concentrations of 2 to 339 fmol/ml. These are comparable to the concentration of opioid peptides in spinal fluid. Both morphine and codeine are present mainly in conjugated form from which the free alkaloids can be released by acid hydrolysis.
