Quantitative GLC determination of codeine in plasma.
A sensitive and accurate GLC method for quantitating codeine in plasma at levels of 50 ng/ml, with limits of detection as low as 5 ng/ml, is described.
Chromatography, Gas↗
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Binding of codeine, morphine, and methadone to human serum proteins.
The binding properties of codeine, morphine (as representative opium alkaloids), and methadone (a synthetic pharmacologically similar compound) were studied with selected human serum proteins. The methodology involved equilibrium and dynamic dialysis using 3H-and/or 14C-labeled compounds. For estimation of the percent binding with equilibrium dialysis, concentrations of the ligand used were approximately therapeutic blood levels and another concentration 30-60 times higher. The percent binding to whole human serum ranged from about 20% for morphine to almost 60% for methadone. Of the human serum proteins investigated, the highest percent binding was found with albumin, except for methadone for which it was beta-globulin III. The affinity for other serum proteins varied with the ligand. In studies with albumin using dynamic dialysis, the plots of nubar divided by free concentration versus nubar were similar for all three ligands studied and had positive slopes, unlike those reported for acidic compounds for which the slope is always negative. In studies of binding of one ligand in the presence of another, significant competition was demonstrated, suggesting that the same binding sites were involved.
Binding, Competitive↗
Quantitative determinations of codeine phosphate, guaifenesin, pheniramine maleate, phenylpropanolamine hydrochloride, and pyrilamine maleate in an expectorant by high-pressure liquid chromatography.
The quantitative determinations of codeine phosphate, guaifenesin, pheniramine maleate, phenylpropanolamine hydrochloride, and pyrilamine maleate in a liquid dosage form are described. All active and inactive ingredients (sodium benzoate and FD&C Yellow No. 5 dye) can be separated with high-pressure liquid chromatography except the two antihistamines, pheniramine maleate and pyrilamine maleate. Pheniramine maleate is determined colorimetrically, and pyrilamine maleate is determined either by difference or spectrophotometrically. The methods are simple short, accurate, and precise. The standard deviations are reported.
Chromatography, High Pressure Liquid↗
Simultaneous quantitation of acetaminophen, aspirin, caffeine, codeine phosphate, phenacetin, and salicylamide by high-pressure liquid chromatography.
A method for the simultaneous quantitation of acetaminophen, aspirin, caffeine, codeine phosphate, phenacetin, and salicylamide was developed. The method is based on reversed-phase high-pressure liquid chromatography with a mobile phase buffered with phosphate (pH 2.3). The procedure not only separated these six active ingredients but also salicylic acid, the major decomposition product of aspirin. The method gave excellent results for three commercial products and a synthetic mixture containing four active ingredients. Lowering the pH increased the retention time of some weak acids and decreased that of some weak bases. Only these changes in the retention times made the separation possible.
Acetaminophen↗
Codeine-induced bronchoconstriction and putative bronchial opiate receptors in asthmatic subjects.
To determine whether a mu opiate agonist can constrict the human airways, the dose of codeine (C) or histamine (H) producing a 40% decrease (PD40) in specific airway conductance (SGAW) was measured in 17 asthmatic and 14 normal subjects. Then, the subjects were skin tested with C and H, and the effect of naloxone (N) and chlorpheniramine (CP) on PD40-C was assessed. In five asthmatic subjects responding to less than 5 mg (16.6 mumol) inhaled C, SGAW was also recorded after oral administration (30 mg) and pharyngeal spraying (5 mg) of C. PD40-C could be determined in 11 of the 17 asthmatics but in none of the normal subjects. This constrictor effect lasted less than 15 min, was unrelated to resting airway caliber, and required a relatively high bronchial sensitivity to H (PD40-H usually less than 0.2 mumol) and high doses of C (11.93 +/- 12.0 mumol). However, in C responders, PD40-C and PD40-H were unrelated. C-induced bronchoconstriction was blunted by N in a dose-dependent fashion and to a mild and inconsistent degree, by CP. Pharyngeal spraying or oral challenge with C failed to change SGAW. Skin sensitivity to H and C was similar in C-responders and non-responders. In conclusion, large doses of inhaled C constrict the airways of asthmatic subjects highly sensitive to H. This effect seems mediated through (mu?) opiate receptors located bronchially rather than centrally, pharyngeally or in the skin. In C-induced bronchoconstriction H liberation plays a contributory but minor role. Skin and bronchial sensitivity to C are unrelated.
Adolescent↗
Genetic analysis of the interethnic difference between Chinese and Caucasians in the polymorphic metabolism of debrisoquine and codeine.
The Far Eastern and Caucasian populations are strikingly different with respect to the debrisoquine/sparteine hydroxylation polymorphism. The number of poor metabolizers, as defined for Caucasians, is very low among Chinese and Japanese. We investigated the molecular basis for this difference by analysis of the CYP2D6 gene in 115 Chinese subjects, combined with phenotypic classification of codeine and debrisoquine metabolism. A correlation between the rates of metabolism of these two drugs and genotype, as analyzed by RFLP using XbaI, was observed among the Chinese. A high frequency (37%) of alleles indicative of gene insertions (reflected by XbaI 44kb fragments) was recorded in the Chinese, but was not associated with the poor metabolizer phenotype, as it is in Caucasians. PCR amplification of part of the CYP2D6 gene with mutation specific primers for CYP2D6A (29A) and CYP2D6B (29B) allelic variants revealed that the XbaI 44kb fragment in Chinese apparently contains a functional CYP2D6 gene, in contrast to the situation among Caucasians. The results provide a molecular explanation of the interethnic difference in the metabolism of drugs affected by the debrisoquine hydroxylation polymorphism.
Adolescent↗
[Determination of morphine and codeine in urine by high-pressure liquid chromatography (author's transl)].
A sensitive and specific method for the determination of morphine and codeine is described. The drugs are adsorbed from urine on Amberlite XAD-2 resin at pH 8.5 and eluted from it with organic solvent. After a clean up the residue is separated by high-pressure-liquid-chromatography on reversed phase column using 0.1 M NaH2PO4 in 25% CH3CN/H2O as mobile phase. The eluted drugs are detected by uv-absorption at 230 nm. The method is sensitive, specific and precise.
Chromatography, High Pressure Liquid↗
Endogenous codeine and morphine are stored in specific brain neurons.
Codeine and morphine have been detected in mammalian brain by radioimmunoassay (RIA), and in brain and other tissues by gas-chromatography/mass-spectrometry (GCMS) in different laboratories. It has been also shown that rat liver can synthesize the skeleton of the morphine molecule, thus suggesting that this alkaloid, which is the prototype of mu-receptor agonists, plays a physiological role in brain. We report the presence of morphine-like immunoreactive compounds inside the cell body, fibers and terminals of neurons in different brain areas. Moreover, neurons localized in the same brain areas were capable of accumulating and storing [3H]morphine slowly infused intracerebroventricularly (i.c.v.) through an osmotic minipump.
Animals↗
Characterization of morphine-specific monoclonal antibodies showing minimal cross-reactivity with codeine.
Six murine monoclonal antibodies against morphine were produced using N-(4-aminobutyl)normorphine as a hapten. Most of the antibodies obtained distinguished the substituents at the 3 and 6 positions of morphine. This property of the antibodies led to a reduction in cross-reactivity with codeine, morphine-3-glucuronide (M-3-G) and morphine-6-glucuronide (M-6-G) to negligible levels. However, one of the antibodies distinguished the substituent only at the 3 position of morphine, which cross-reacted with M-6-G, naloxone and naltrexone. In the competitive inhibition enzyme-linked immunosorbent assay, morphine was detected at concentrations as low as circa 100 pg/ml.
Animals↗
Toxicological investigations of cases of death involving codeine and dihydrocodeine.
Drug levels in post-mortem specimens from 6 cases of poisoning involving codeine or dihydrocodeine have been determined using a direct extraction method followed by gas liquid chromatography. The relevant case histories are described. A preliminary qualitative investigation of dihydrocodeine metabolism has been described involving the analysis of urine samples by thin layer and gas chromatography.
Adult↗
High-performance liquid chromatographic determination of morphine, morphine-3-glucuronide, morphine-6-glucuronide and codeine in biological samples using multi-wavelength forward optical detection.
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.
Chromatography, High Pressure Liquid↗
Evidence for CYP2D1-mediated primary and secondary O-dealkylation of ethylmorphine and codeine in rat liver microsomes.
The purpose of the present study was to investigate the role of specific CYPs responsible for the O-dealkylation of ethylmorphine (EM) and codeine (CD) to morphine (M), as well as that of norethylmorphine (NEM) and norcodeine (NCD) to normorphine (NM) in rat liver microsomes. Liver microsomes metabolize EM and CD to M, and NEM and NCD to NM, in the presence of an NADPH-generating system. The metabolites of EM and CD were determined by HPLC with UV and electrochemical detection. In the present study, the role of CYP2D1 in O-dealkylation of EM/NEM and CD/NCD was investigated by use of specific antiCYP antibodies. When testing rabbit antirat CYP2D1, 2E1, 2C11, and 3A2 antibodies, only the antiCYP2D1 antibody inhibited the EM/NEM and CD/NCD O-dealkylase activities significantly. The maximum inhibition achieved was approximately 80% at a protein ratio (IgG to microsomes) of 10:1, p = 0.001. The contribution of CYP2D1 to the O-dealkylation of EM/NEM and CD/NCD was further confirmed by use of the specific CYP2D1 inhibitors quinine and propafenone. Five microM of quinine inhibited the EM/NEM and CD/NCD O-dealkylase activities by approximately 80%. The CYP3A inhibitor troleandomycin (TAO) failed to inhibit the CYP2D1 catalyzed reaction, but did inhibit the N-demethylation of EM and CD. The O-dealkylation of NEM and NCD was also impaired in Dark Agouti rat (DA) liver microsomes. Taken together, the immunoinhibition and chemical-inhibitor studies of rat liver microsomes provided convincing evidence for the involvement of CYP2D1, the rat counterpart of human CYP2D6, in the metabolism of EM/NEM and CD/NCD to the corresponding O-dealkylated metabolites.
Animals↗
Pharmacological characterization of morphine-6-sulfate and codeine-6-sulfate.
Morphine-6-sulfate (M6S) and codeine-6-sulfate (C6S) are mu-selective opiates which have been isolated from brain. M6S is an effective analgesic, with a 30-fold greater potency than morphine in the mouse radiant heat tailflick assay and similar to the active morphine metabolite morphine-6beta-glucuronide (M6G). M6S analgesia is reversed by 3-methoxynaltrexone at low antagonist doses which are inactive against morphine, suggesting that M6S may be acting through the same mechanisms as M6G. Consistent with this possibility, antisense mapping of the MOR-1 clone revealed that M6S analgesia was lowered by probes targeting exon 2 and not by targeting exon 1, a sensitivity profile similar to that of M6G and not morphine. C6S also has analgesic activity at doses approximately 10-fold greater than M6S. However, its characterization was impeded by the appearance of seizures at doses below full analgesic activity. Thus, M6S is a potent analgesic with pharmacological properties similar to M6G. C6S has limited utility due to its high level of toxicity.
Analgesics, Opioid↗
Separation of ibuprofen, codeine phosphate, their degradation products and impurities by capillary electrophoresis. I. Method development and optimization with fractional factorial design.
A capillary electrophoresis method has been developed and optimized for the separation of ibuprofen, codeine phosphate and their main degradation products and impurities. In the course of developing the method, it was found that micellar electrokinetic capillary chromatography was necessary for the separation of the eleven peaks. A fractional factorial design was used for the optimization of the experiments. Six process parameters were varied at two levels: the concentration of sodium dodecyl sulfate (SDS), the pH, the concentration of acetonitrile, the concentration of boric acid, the field strength and the temperature. All these factors had a significant effect on the migration time and resolution. The optimum conditions were found to be a borate buffer of 40 mM H3BO3 at pH 10 with the addition of 40 mM SDS and 9% acetonitrile, a field strength of 515 V/cm and a temperature of 25 degrees C. This resulted in baseline separation of the eleven peaks within 12 min.
Acetonitriles↗
Separation of ibuprofen, codeine phosphate, their degradation products and impurities by capillary electrophoresis. II. Validation.
A micellar electrokinetic chromatography method for the determination of ibuprofen and codeine phosphate hemihydrate and their degradation products and impurities in a commercial tablet formulation has been validated. The validation has been performed according to the International Conference of Harmonisation's guidance on the validation of analytical methods, and selectivity, linearity, accuracy, precision, detection limit, quantitation limit, robustness and range test were performed to determine the suitability of the method. It was possible to use the fractional factorial design model from the optimisation of the method to draw conclusions about its robustness. The results confirm that the method is highly suitable for its intended purpose.
Chemistry, Pharmaceutical↗
Full and fractionated experimental designs for robustness testing in the high-performance liquid chromatographic analysis of codeine phosphate, pseudoephedrine hydrochloride and chlorpheniramine maleate in a pharmaceutical preparation.
This paper describes the testing of a saturated factorial design using a full factorial design. Saturated factorial designs are often used to test the robustness of high-performance liquid chromatography (HPLC) methods, however they are based on several assumptions. A full factorial design relies on fewer assumptions and hence could be used to evaluate the effectiveness of the saturated design. Both designs were used to test a gradient HPLC method for the assay of codeine phosphate, pseudoephedrine hydrochloride and chlorpheniramine maleate. Six HPLC conditions, including wavelength, mobile phase pH and ion pairing reagent concentration were tested using the saturated design. Three of these factors were selected for full evaluation using a full factorial design. The results showed that the main effects calculated by each design were comparable. However, the saturated design showed higher standard errors, probably due to the effects of changing several more factors. One interaction effect was indicated as a confounding effect by the saturated design and this was confirmed by the calculation of the same interaction effect using the full design. Overall the method was shown to be robust under the variety of HPLC conditions tested.
Chlorpheniramine↗
Endogenous codeine and morphine in anorexia and bulimia nervosa.
The endogenous plasma alkaloids codeine and morphine were shown to be elevated in patients with anorexia nervosa and bulimia nervosa compared to control subjects. The role of these opioids in the pathophysiology of these eating disorders is discussed in relation to an auto-addiction opioid model. This model proposes that endogenous opioids are released during an initial period of dieting and reinforce a state of starvation dependence [1,2].
Adolescent↗
Codeine intoxication in childhood.
Clinical reports on 430 children with acute codeine intoxication are evaluated. Of 234 children who had taken more than 5 mg/kg body-weight, 8 had respiratroy arrest necessitating intubation and artificial ventilation; 2 of them died. In all other cases the intoxication produced one or more of the following symptoms: somnolence, ataxia, miosis, vomiting, rash, swelling, and itching of the skin, but no life-threatening side-effects. Close supervision of respiration is the main principle of management when more than 2 mg codeine/kg body-weight has been taken. Gastric voiding may be useful if done soon after ingestion. Charcoal and purgatives should be given in all cases.
Antitussive Agents↗