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PubMed2000

A comparison of rectal and intramuscular codeine phosphate in children following neurosurgery.

Codeine is frequently used for postoperative analgesia in children. Intramuscular injections are not ideal and the rectal route may be preferable. We compared rectal and intramuscular codeine administered following neurosurgery. 20 children (over 3 months) undergoing elective neurosurgical procedures, were randomized to receive either rectal or intramuscular codeine phospate (1 mg.kg-1) at the end of the procedure. Serum levels of codeine and morphine were assayed at intervals following administration (0, 30, 60, 120, 240 min). Fentanyl was the intraoperative analgesic and postoperative rescue analgesia was paracetamol, diclofenac and intramuscular codeine. The Children's Hospital of Eastern Ontario Pain Scale was used to assess analgesia. Peak codeine levels in both groups were observed at 30 min and morphine levels were consistently low. The plasma codeine levels were significantly greater at 30 and 60 min following intramuscular injection, and were associated with slightly better analgesia scores, but did not reach statistical significance. However, the peak plasma level occurred at similar times in both groups. Codeine is absorbed as rapidly via the rectal route compared with the intramuscular route but the peak levels are lower.

Absorption↗
PubMed2000

The effects of collection methods on oral fluid codeine concentrations.

The use of a variety of alternative biological specimens such as oral fluid for the detection and quantitation of drugs has recently been the focus of considerable scientific research and evaluation. A disadvantage of drug testing using alternative specimens is the lack of scientific literature describing the collection and analyses of these specimens and the limited literature about the pharmacokinetics and disposition of drugs in the specimen. Common methods of oral fluid collection are spitting, draining, suction, and collection on various types of absorbent swabs. The effect(s) of collection techniques on the resultant oral fluid drug concentration has not been thoroughly evaluated. Reported is a controlled clinical study (using codeine) that was designed to determine the effects of five collection techniques and devices on oral fluid codeine concentrations. The collection techniques were control (spitting), acidic stimulation, nonacidic stimulation, and use of either the Salivette or the Finger Collector (containing Accu-Sorb) oral fluid collection devices. Preliminary data were collected from two subjects using the Orasure device. The in vitro drug recovery was also evaluated for the Salivette and the Finger Collector devices. With the exception of a single time point, codeine concentrations in specimens collected by the control method (spitting) were consistently higher than concentrations in specimens collected by the other methods. The control collection concentrations averaged 3.6 times higher than concentrations in specimens collected by acidic stimulation and 1.3 to 2.0 higher than concentrations in specimens collected by nonacidic stimulation or collection using either the Salivette or the Finger Collector devices. When calculated using oral fluid codeine concentrations from the clinical study, the elimination rate constant, t(1/2), AUC and the peak oral fluid concentrations demonstrated device differences. The slope of the elimination curve for codeine using the acidic collection method exceeded that of the other four methods. As a result, the t(1/2) for the acidic method was significantly less than that of the control method (1.8 vs. 3.0 h, respectively). Oral contamination contributed to the control method having higher AUC than that calculated using the other methods. There was considerable variation in peak codeine concentrations between devices and between individuals within each collection method. When samples were collected simultaneously with the Salivette and the Finger Collector, the mean codeine concentrations were similar. We were able to recover > or = 500 microL of oral fluid from 81.8% of the clinical samples collected with the Salivette. However, we were able to recover this volume from only 25.5% of the samples collected with the Finger Collector. In addition, the in vitro drug recoveries were lower using the Finger Collector. When oral fluid was collected nearly simultaneously by the control method and by use of the Salivette, mean control codeine concentrations were 2.3 times higher, but the duration of detection was similar for both methods.

Area Under Curve↗
PubMed1986

Treatment of narcolepsy with codeine.

The effectiveness of codeine as a treatment for the excessive daytime sleepiness of narcolepsy was studied in two experimental trials. In an open trial of codeine in five narcoleptic subjects, dramatic clinical improvement was reported. However, all-night polysomnography and maintenance of wakefulness tests before and after codeine showed no significant differences. A double-blind placebo-codeine trial was conducted in which eight narcoleptic subjects received codeine for 1 week and placebo for 1 week in a random order. During the week they kept a diary, and on the sixth evening and for 10 h following awakening on the seventh day they were monitored by radiotelemetry in the sleep laboratory for electroencephalogram, electro-oculogram, and electromyogram. The results were analyzed for sleep stages as well as four levels of wakefulness. The results showed no significant differences in any of the objective sleep or wakefulness parameters. However, the diaries showed significantly fewer naps during the week on codeine as compared with the placebo week. Eighteen of 27 narcoleptic patients treated with codeine report clinical improvement. Codeine consistently results in subjective clinical improvement. However, this is not reflected in the objective measures generally used to assess daytime sleepiness.

Adult↗
PubMed2000

On the assessment of drug metabolism by assays of codeine and its main metabolites.

Codeine and its main metabolites appear to have advantages for assessing drug metabolic phenotypes. The authors have further developed a high-performance liquid chromatography (HPLC) method for the quantification of codeine and six of its metabolites in urine. Quantification was performed by electrochemical detection for morphine, normorphine, morphine-6-glucuronide, and the internal standard 4-O-methyldopamine; and by ultraviolet detection for codeine, norcodeine, and morphine-3-glucuronide. The method had a detection limit of 2 nmol/L(-1) for morphine and normorphine, 4 nmol/L(-1) for morphine-6-glucuronide, 3 nmol/L for the internal standard, 20 nmol/L(-1) for morphine-3-glucuronide, and 60 nmol/L(-1) for codeine and norcodeine. The coefficients of variations were <9% for intraday and <10% for interday analyses. The recovery of codeine and its metabolites ranged from 55% (for morphine-3-glucuronide) to 90% (for codeine, norcodeine, morphine, and morphine-6-glucuronide). Eleven healthy volunteers were phenotyped for CYP2D6 using codeine as well as debrisoquine and dextromethorphan. Ten subjects were extensive metabolizers (EM) and one a poor metabolizer (PM) of codeine, debrisoquine, and dextromethorphan. Significant correlations between the metabolic ratios (MRs) of the different probe drugs were obtained (r2 > 0.95, p < 0.001). This HPLC method is simple, sensitive, accurate, and reproducible for assessing the CYP2D6 phenotype.

Adult↗
PubMed1994

Carbamazepine and cigarette smoking induce differentially the metabolism of codeine in man.

The inducibility of codeine metabolism by carbamazepine (CBZ) and cigarette smoking has been investigated. A single oral dose of 25 mg of codeine was given to seven epileptic patients before and after 3 weeks' regular CBZ treatment (400-600 mg per day). Codeine was also given to nine volunteers who were heavy smokers (20 cigarettes per day) and to nine non-smokers as controls. All subjects were found to be extensive metabolizers of codeine by O-demethylation. Urine was collected over 8 h following codeine intake. Codeine and the metabolites were analysed with HPLC. CBZ significantly increased the urinary excretion of the N-demethylated metabolite, norcodeine (NC) which led to a significant decrease in the metabolic ratio (MR) for N-demethylation. The O-demethylation was not significantly altered. The excretion of normorphine, an active metabolite formed through both O- and N-demethylation of codeine increased by almost three-fold after CBZ treatment. Contrary to CBZ treatment, cigarette smoking slightly but significantly induced the glucuronidation of codeine as shown by a decreased MR for glucuronidation in the smokers, while the O- and N-demethylations were not significantly changed as indicated by the similar MRs in smokers and in non-smokers. These results suggest that CBZ and cigarette smoking selectively induce different metabolizing enzymes. The polymorphic O-demethylation is relatively stable to these factors.

Adolescent↗
PubMed1986

Comparative disposition of codeine and pholcodine in man after single oral doses.

Four healthy male subjects received single oral doses of 15, 30 and 60 mg of codeine and pholcodine according to a balanced cross-over design with an interval of 7 days between the six treatments. Blood samples were collected for 8 h after each drug administration. In phase 2 of the study six different male volunteers received single oral doses of 60 mg of codeine and pholcodine with a 14 day interval between successive drug treatments. Blood was sampled for 12 h after codeine and 121 h after pholcodine administration. Plasma concentrations of free (unconjugated) and total (unconjugated plus conjugated) codeine, pholcodine and morphine were determined by radioimmunoassay and selected pharmacokinetic parameters were derived from these data. Pharmacokinetics of both drugs were independent of dose. Codeine was absorbed and eliminated relatively rapidly [elimination t1/2 = 2.3 +/- 0.4 h (mean +/- s.d.)]. While codeine kinetics were adequately described by a one-compartment open model with first-order absorption, a two-compartment model was required to describe pholcodine elimination from plasma (t1/2,z = 37.0 +/- 4.2 h). Plasma concentrations of conjugated codeine were much greater than those of the unconjugated alkaloid. By contrast, pholcodine appeared to undergo little conjugation. Biotransformation of codeine to morphine was evident in all subjects, although the extent of this metabolic conversion varied considerably between subjects. Morphine was not detectable in the plasma of any subject after pholcodine administration.

Administration, Oral↗
PubMed1989

Codeine O-demethylation co-segregates with polymorphic debrisoquine hydroxylation.

1. A single oral dose of codeine (25 mg) was given to 132 healthy Swedish Caucasians who had previously been phenotyped with respect to debrisoquine hydroxylation. The 'metabolic ratios' (MR) in urine of codeine O-demethylation (codeine/(morphine (M) + morphine-3- and 6-glucuronides (M3G and M6G) + normorphine], N-demethylation (codeine/(norcodeine (NC) + norcodeine glucuronide + normorphine (NM]) and glucuronidation (codeine/codeine-6-glucuronide (C6G] were calculated following h.p.l.c. analysis of urine samples collected over 8 h. 2. There was a significant correlation between the log MR for debrisoquine hydroxylation and the log MR for codeine O-demethylation (rs = 0.77, P less than 0.001). The poor debrisoquine hydroxylators had MRs of codeine O-demethylation between 8.3 and 55.1, while the values for extensive hydroxylators were between 0.4 and 5.5. 3. The poor debrisoquine hydroxylators excreted significantly less M, M3G, M6G and NM, while the urinary recovery of C6G and NC was significantly higher in these subjects compared to the extensive hydroxylators. 4. The MRs for glucuronidation and N-demethylation did not exhibit a bimodal distribution, and were not related to the MR of debrisoquine hydroxylation. 5. No associations were found between sex, body-weight, smoking habits, age, urine volume or urine pH and the O-demethylation of codeine. 6. The O-demethylation of codeine to form M appears to be under the same polymorphic genetic control as the 4-hydroxylation of debrisoquine.

Adolescent↗
PubMed1991

A comparison of the pharmacokinetics of codeine and its metabolites in healthy Chinese and Caucasian extensive hydroxylators of debrisoquine.

1. The kinetics of codeine and metabolites were studied in eight unrelated healthy Chinese subjects following a single oral dose of 50 mg codeine phosphate. The data were compared with those from eight Caucasian subjects who were matched with the Chinese group according to their metabolic ratio (MR) of debrisoquine. 2. Mean values of Cmax (445 nmol l-1) and AUC (1660 nmol l-1 h) of codeine in the Chinese were significantly higher than those in the Caucasians (292 nmol l-1 and 1010 nmol l-1 h). Thus plasma clearance was significantly lower (P less than 0.02) and the plasma half-life was longer (P less than 0.05) in the Chinese. 3. Partial clearance by glucuronidation was significantly lower (0.79 +/- 0.14 s.d. vs 1.42 +/- 0.48 s.d. 1 h-1 kg-1) in Chinese than in Caucasians. 4. The total urinary recovery of drug-related material in 48 h urine was similar in Chinese (82.2%) and Caucasians (84.4%). The recovery of unchanged codeine was significantly higher in Chinese (5.7%) than in Caucasians (3.3%). 5. The AUC ratios of codeine relative to its 6-glucuronide, morphine and norcodeine were 1:9, 35:1 and 4:1, respectively in Chinese. The corresponding ratios in Caucasians were 1:15, 50:1 and 6:1. 6. There was no significant difference between Chinese and Caucasians in the renal clearances of codeine and its primary metabolites. 7. Large interethnic differences in the kinetics of codeine have been shown. The Chinese are less able to metabolise codeine mainly because of a lower efficiency in glucuronidation.

Administration, Oral↗
PubMed1995

Codeine-induced histamine release in intact human skin monitored by skin microdialysis technique: comparison of intradermal injections with an atraumatic intraprobe drug delivery system.

BACKGROUND: The skin microdialysis technique makes it possible to measure histamine release in intact human skin in vivo directly. In this study we have used the microdialysis technique to characterize histamine release by codeine after intracutaneous injections and following skin challenge by a novel atraumatic delivery technique. OBJECTIVE: The purpose of the study was to compare histamine release in human skin by codeine, delivered by an intraprobe drug delivery system (IPD) and intracutaneous injections (ICT), with respect to dose-response relations, kinetics of histamine appearance and decay, correlations between histamine release and skin responses, and reproducibility. METHODS: Hollow dialysis fibres were inserted intradermally in 12 healthy subjects. Twelve fibres were inserted in each subject, six fibres in each arm. Each fibre was perfused at a rate of 3 microM/min, and samples were collected in 2 min fractions. By the IPD technique, codeine was administered to the skin by adding codeine to the perfusion medium. Sequential IPD challenges were performed in one arm, and ICTs were done on the other arm. RESULTS: Sixfold serial dilutions of codeine (0.01-3 mg/mL) caused a significant dose-related histamine release by ICT and IPD. Peak histamine release was found within the first 4 min after skin challenge by ICT and IPD, followed by a fast decline with a dialysate histamine half life of approximately 2-3 min. Peak histamine release was linearly correlated with cumulative release of the 20 min sampling period, and histamine release correlated with weal size. The coefficient of variation on peak histamine release was 18.9% and 4.8% for codeine ICT and IPD, respectively. CONCLUSION: We have described in detail codeine-induced histamine release in intact human skin in vivo by the microdialysis technique. It was possible to administer codeine atraumatically to the skin by intraprobe delivery. The skin microdialysis technique opens up possibilities for measurement of inflammatory mediators release in normal and diseased skin, and it will be possible to deliver immunopharmacologically active drugs to the skin by intraprobe delivery.

Adult↗
PubMed2004

Probable codeine phosphate-induced seizures.

OBJECTIVE: To report a case of seizure activity associated with oral codeine phosphate administered for analgesia in an elderly woman with end-stage renal disease. CASE SUMMARY: A 73-year-old Taiwanese woman with end-stage renal disease received oral codeine phosphate 30 mg 4 times daily for her back and rib pain without adjustment of her dosage regimen. Seven days after starting codeine therapy, the woman became stuporous and developed tonic-clonic seizures. After phenytoin initiation, codeine discontinuation, and naloxone administration, the seizures did not recur. DISCUSSION: Codeine is a frequently used opioid analgesic, especially when pain control with acetaminophen or nonsteroidal antiinflammatory drugs fails. Although seizures associated with codeine have been reported, pertinent data are very limited and the exact mechanism is unknown. An objective causality assessment indicated the seizure to be a probable drug-related event in this patient. CONCLUSIONS: Elderly patients with end-stage renal disease may be predisposed to seizures with higher doses of codeine phosphate. It is imperative to adjust the codeine dosage regimen based on patients' renal function to avoid the potential toxicity with overdose.

Aged↗
PubMed2000

Double blind randomized placebo control trial of controlled release codeine in the treatment of osteoarthritis of the hip or knee.

OBJECTIVE: Pain is the cardinal feature of osteoarthritis (OA), and with advancing disease there is loss of function and increasing pain even at times of joint rest. Few studies have evaluated the role of opioid analgesics in treating the pain of OA. METHODS: This randomized, double blind, parallel group study compared the efficacy and safety of a 12 hourly controlled release codeine formulation (Codeine Contin) with placebo in patients with chronic pain due to OA of the hips and/or knees. The 4 week treatment period, following an analgesic washout phase of 2-7 days, included weekly clinic evaluations, at which the dose was escalated as appropriate, and daily patient diary completion. Pain (daily), stiffness, and physical function (weekly) were assessed using the multidimensional, self-administered WOMAC (visual analog scale version) questionnaire. RESULTS: Sixty-six eligible patients completed the study. The mean initial and final daily doses of controlled release codeine were 50 mg every 12 h at baseline and 159 mg every 12 h at the final assessment. All variables in the efficacy analysis indicated superiority of controlled release codeine over placebo. The WOMAC pain scale showed an improvement of 44.8% over baseline in the controlled release codeine group compared with 12.3% taking placebo (p = 0.0004). For the WOMAC stiffness and physical function scales the improvements over baseline on controlled release codeine were 47.7% and 49.3%, respectively compared with 17.0% and 17.0%, respectively, with placebo (p = 0.003; p = 0.0007). Controlled release codeine was also significantly better than placebo on measures of sleep quality and requirement for supplemental acetaminophen. CONCLUSION: Single entity controlled release codeine is an effective treatment for pain due to OA of the hip or knee.

Acetaminophen↗
PubMed2000

Over-the-counter codeine use in Iceland: the impact of increased access.

BACKGROUND: The objective of this study was to test the assumption that liberalizing community pharmacy ownership in Iceland would lead to increased irrational use of over-the-counter pain relievers containing codeine. METHODS: Based on this assumption we built and tested a model using an interrupted time series design that contrasts the monthly sales data for over-the-counter pain relievers containing codeine before and after the legislation took effect. RESULTS: The total use of over-the-counter pain relievers containing codeine as well as those containing paracetamol and codeine has risen steadily throughout the period under study. The interrupted time series did not show a substantial effect from the legislative change on the use of all over-the-counter codeine pain relievers, paracetemol with codeine, and aspirin with codeine combinations. CONCLUSION: The assumption that increased access leads to irrational use of over-the-counter medicines is not substantiated in the case of over-the-counter pain relievers containing codeine.

Analgesics, Opioid↗
PubMed1975

Further studies on self-administration of antipyretic analgesics and combination of antipyretic analgesics with codeine in rhesus monkeys.

The possible reinforcing effect of acetylsalicylic acid (ASA) was studied in a group of rhesus monkeys that had no history of self-administration of drugs. Rates of lever pressing were compared under conditions in which each lever-pressing response resulted in an infusion of saline, an infusion of saline plus delivery of a food pellet or an infusion of ASA (0.4, 1.0, 2.5 OR 5.0 MG/KG /infusion). Responding was engendered and maintained by the delivery of food pellets but not by infusions of saline alone nor by ASA; however, responding was subsequently engendered and maintained in these monkeys by codeine (0.05 mg/kg/infusion). In another group of monkeys that had been trained to respond under a 10-response fixed-ratio schedule of i.v. infusions of codeine, the possible reinforcing effects of aminophenazone, phenylbutazone and of combinations of each of these drugs with codeine were studied. Aminophenazone and phenylbutazone (0.4-5.0 mg/kg/infusion) did not maintain responding previously engendered by codeine. Mixtures of aminophenazone and phenylbutazone with codeine decreased the number of codeine self-administrations. Thus, codeine intake was reduced when aminophenazone and phenylbutazone were added to codeine in the solution to be self-administered. These experiments suggest that antipyretic analgesics are not effective in reinforcing behavior in the rhesus monkey.

Aminopyrine↗
PubMed2004

[Problem forte--is paracetamol-codeine combination rational?].

BACKGROUND: Combination drugs containing codeine and paracetamol are widely prescribed in Norway. MATERIAL AND METHODS: We reviewed relevant literature identified through searches on Medline or found in the reference lists of important articles. RESULTS: Codeine mediates its analgesic effect through the active metabolite morphine, a reaction which is catalysed by the cytochrome P450-isoenzyme CYP2D6. Approximately 7-10 % of the population does not express functional CYP2D6; for them codeine have no analgesic effect. They may, however, experience side effects from codeine. Used alone, codeine is an inefficient analgesic. Meta-analyses have shown little therapeutic advantage by adding codeine to paracetamol. INTERPRETATION: Codeine is an opiate with uncertain and unpredictable effects. The therapeutic benefit from the codeine component in combination with paracetamol is small, even in single dose evaluations. In chronic use, the therapeutic efficacy is most likely outweighed by side effects, including development of tolerance and abuse.

Acetaminophen↗
PubMed1991

Effect of codeine on rat and guinea pig tracheal ciliary beat frequency.

Codeine, the basic antitussive drug, has generally been thought to impair mucociliary function. Using the photodetection method the effect of codeine on mucociliary function was studied in rat after local and systemic administration and in guinea pig after systemic administration. In vitro rat tracheal ciliary beat frequency (CBF) was measured up to 40 min. There was 24.6 +/- 2.5% and 26.6 +/- 1.6% decrease in CBF after 1 mg/ml and after 10 mg/ml codeine solutions, respectively. In vivo codeine was administered in single i.v. doses of 10 and 15 mg/kg. No statistically significant differences were found in CBF responses, although there was a CBF decreasing tendency after the 15 mg/kg dose. The total follow-up time was 120 min. In guinea pig, 10 days s.c. codeine administration in daily doses of 3, 10 and 30 mg/kg had no effect on CBF. Although codeine was used in much higher concentrations than tissues concentrations after therapeutic doses of codeine, the effects on CBF were minimal. So it can be concluded that the generally accepted ciliostatic effect of codeine is overestimated.

Animals↗
PubMed1987

Comparison of diflunisal and an aspirin-codeine combination in the management of patients having one-visit endodontic therapy.

One hundred seventy-nine patients with asymptomatic or mildly symptomatic endodontic disease had single-visit therapy and were given either diflunisal (n = 94) or aspirin with codeine (n = 85) to control posttreatment pain. In this open-label, randomized study, diflunisal was judged superior to the aspirin-codeine combination in all major categories evaluated. Of patients receiving diflunisal, 93.6% needed the medication for only one day. In contrast, 77.7% of patients receiving aspirin with codeine needed the medication for only one day. Almost 64% of patients receiving diflunisal needed only one dose, while 32.9% of patients using aspirin with codeine needed only one dose. Four or more doses were required by 5.3% of patients receiving diflunisal and by 23.5% of patients receiving the aspirin-codeine combination. In patients receiving diflunisal, 20.2% experienced side effects. In contrast, 29.4% of patients receiving aspirin with codeine reported side effects. Thirty-five percent of patients receiving diflunisal rated the analgesic as excellent; 5.3% rated it as fair or poor. In contrast, 12.9% of patients receiving aspirin with codeine rated the analgesic combination as excellent; another 12.9% rated it as fair or poor. Diflunisal was found to be generally effective and well-tolerated, and superior to aspirin with codeine in the management of pain from endodontic treatment.

Adolescent↗
PubMed1994

Endogenous codeine and morphine in poor and extensive metabolisers of the CYP2D6 (debrisoquine/sparteine) polymorphism.

Codeine and morphine are endogenous substances. Following administration of exogenous codeine the biotransformation to morphine is catalyzed by CYP2D6, which exhibits a genetic so-called debrisoquine/sparteine polymorphism which is expressed in two phenotypes, the extensive and poor metaboliser phenotypes. Poor metabolisers form only trace amounts of morphine. If endogenous morphine is biosynthesised in humans via similar routes as in the poppy plant, two of the steps involved are mediated by CYP2D6, namely thebaine O-demethylation to oripavine and codeine O-demethylation to morphine. Poor metabolisers should therefore have a much lower endogenous morphine formation than extensive metabolisers. The urinary excretion of endogenous codeine and morphine were investigated in 20 extensive and 20 poor metabolisers of CYP2D6. Substantial interindividual variation in codeine (7-6851 pmol/24 hr) and morphine (32-35471 pmol/24 hr) excretion was observed. However, there were no phenotype-related differences in endogenous codeine and morphine excretion. Administration of the competitive CYP2D6 inhibitor quinidine had no significant effect on endogenous codeine and morphine excretion in extensive metabolisers. In conclusion, in contrast to exogenous codeine O-demethylation to morphine CYP2D6 appears not to be involved in the biosynthesis of morphine in humans.

Adult↗
PubMed1996

Microsomal codeine N-demethylation: cosegregation with cytochrome P4503A4 activity.

Codeine is metabolized by glucuronidation, by O-demethylation to morphine, and by N-demethylation to norcodeine. The enzyme responsible for the O-demethylation to morphine has been identified as cytochrome P4502D6 (CYP2D6). The purpose of the present study was to identify the specific P450 enzyme responsible for codeine N-demethylation. Microsomal preparations (250 pmol of P450) obtained from 12 human liver donors were incubated with 20 microM codeine and analyzed for norcodeine formation. Codeine N-demethylation activity was linearly correlated with nifedipine oxidation activity (r = 0.90, p < 0.001), a marker of CYP3A4, but not with codeine O-demethylation, a marker of CYP2D6. Preincubation with troleandomycin (50 microM), or gestodene (50 microM) inhibitors of CYP3A4, decreased the rate of production of norcodeine by 60 and 45% compared to control values, respectively. Similarly, ketoconazole (10 microM) and erythromycin (10 microM) inhibited codeine N-demethylation by 75 and 35%, respectively. In contrast, the presence of quinidine, sulfaphenazole, or diethyldithiocarbamate in the incubation mixture had no effect on norcodeine formation. Preincubation with antibodies raised to CYP3A4 (5 mg lgG/nmol P450) caused 96% inhibition of norcodeine production, whereas preimmune IgG or antibodies raised to CYP2A6 and CYP2C had no effect. Additionally, significant norcodeine production was observed with purified CYP3A4 derived from human liver microsomes. In conclusion, codeine N-demethylation activity cosegregates with CYP3A4 activity. Coadministration of codeine with selective inhibitors of CYP3A4 may result in increased morphine production and enhanced pharmacodynamic effects due to shunting down the CYP2D6 pathway.

Aryl Hydrocarbon Hydroxylases↗