Pharmacokinetics and metabolism of codeine in humans

Vree, T. B.; Wissen, C.P.W.G.M. Verwey-van

doi:10.1002/bdd.2510130607

Cited by 98 publications

(57 citation statements)

References 32 publications

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“…Both drugs are substrates of cytochrome CYP2D6 and compete with fluoxetine and norfluoxetine as substrates for CYP2D6. 17,18 On discontinuation of fluoxetine, codeine, and tramadol, QTc duration normalized to 434 ms, and TdP did not recur. Genetic screening for CYP2D6 revealed that she was an extensive metabolizer of CYP2D6 with genotype CYP2D6*1/*1.…”

Section: Clinical Studiesmentioning

confidence: 98%

Slow Delayed Rectifier Potassium Current Blockade Contributes Importantly to Drug-Induced Long QT Syndrome

Veerman

Verkerk

Blom

et al. 2013

Circ: Arrhythmia and Electrophysiology

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Background-Drug-induced long QT syndrome is generally ascribed to inhibition of the cardiac rapid delayed rectifier potassium current (I Kr ). Effects on the slow delayed rectifier potassium current (I Ks ) are less recognized. Triggered by a patient who carried the K422T mutation in KCNQ1 (encoding the α-subunit of the I Ks channel), who presented with excessive QT prolongation and high serum levels of norfluoxetine, we investigated the effects of fluoxetine and its metabolite norfluoxetine on I Ks . Methods and Results-ECG data from mutation carriers and noncarriers revealed that the K422T mutation per se had mild clinical effects. Patch clamp studies, performed on HEK293 cells, showed that heterozygously expressed K422T KCNQ1/ KCNE1 channels had a positive shift in voltage dependence of activation and an increase in deactivation rate. Fluoxetine and its metabolite norfluoxetine both inhibited KCNQ1/KCNE1 current, with norfluoxetine being the most potent. Moreover, norfluoxetine increased activation and deactivation rates. Computer simulations of the effects of norfluoxetine on I Ks and I Kr demonstrated significant action potential prolongation, to which I Ks block contributed importantly. Although the effects of the mutation per se were small, additional I Ks blockade by norfluoxetine resulted in more prominent QTc prolongation in mutation carriers than in noncarriers, demonstrating synergistic effects of innate and drug-induced I Ks blockade on QTc prolongation. Conclusions-I

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Section: Clinical Studiesmentioning

confidence: 98%

Slow Delayed Rectifier Potassium Current Blockade Contributes Importantly to Drug-Induced Long QT Syndrome

Veerman

Verkerk

Blom

et al. 2013

Circ: Arrhythmia and Electrophysiology

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“…The half-life of codeine is 1.47 8 0.32 h, that of C-6-G 2.75 8 0.79 h. The plasma AUC of C-6-G is approximately 10-fold higher than that of codeine. Protein binding of codeine and C-6-G in vivo was 56.1 8 2.5 and 34.0 8 3.6%, respectively [68] . Codeine metabolic pathways are shown in figure 3 .…”

Section: Codeinementioning

confidence: 99%

“…Quinidine-induced inhibition of codeine O-demethylation is ethnically dependent with the reduction being greater in the Caucasians. Studies performed to date [69][70][71][72][73][74][75][76][77] indicate that codeine analgesia depends on CYP2D6 polymorphism and morphine and the formation of its glucuronides, but codeine and its metabolites (C-6-G and NORC) also contribute to the analgesic effects [66][67][68] .…”

Section: Codeinementioning

confidence: 99%

CYP2D6 in the Metabolism of Opioids for Mild to Moderate Pain

Leppert

2011

Pharmacology

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In most cancer patients, pain is successfully treated with pharmacological measures using opioid analgesics for moderate to severe pain (strong opioids) alone or in combination with adjuvant analgesics (coanalgesics). Opioids for mild to moderate pain (weak opioids) are usually recommended in the treatment of cancer pain of mild to moderate intensity. There is a debate whether the second step of the WHO analgesic ladder comprising weak opioids such as tramadol, codeine and dihydrocodeine is still needed for the treatment of cancer and chronic pain since low doses of strong opioids show similar efficacy. However, many patients with mild, moderate and in some cases strong pain intensity are still successfully treated with weak opioids. All these drugs are metabolized through CYP2D6, an important enzyme for approximately 25% of all drugs administered in clinical practice. The aim of this review is to summarize data on the impact of CYP2D6 polymorphism on pharmacokinetics, pharmacodynamics and adverse effects of weak opioids.

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“…It is metabolized by conjugation to codeine-6-glucuronide and to a minor extent is biotransformed via O-demethylation to morphine and via N-demethylation to norcodeine. 5 Codeine-6-glucuronide is the major metabolite found in urine, whereas codeine is excreted only as a small proportion of the original dose.…”

Section: Discussionmentioning

confidence: 99%

Codeine Intoxication in the Neonate

Magnani

Evans

1999

Pediatrics

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ABSTRACT. Although opiates can provide patients with relief from pain and the discomfort of cough, the routine prescription of these drugs for infants demands caution and concern. Infants, particularly neonates, are not merely small adults requiring smaller dosages, but rather uniquely different patients. Neonates present with an immature physiology and biochemistry with respect to drug metabolism. We report a case of codeine intoxication in the neonate, in which the drug was prescribed for cough control during an emergency department visit. Pediatrics 1999;104(6). URL: http://www.pediatrics.org/ cgi/content/full/104/6/e75; codeine, neonate, toxicity, morphine, fatality. CASE REPORT Baby Z was born at 36 weeks' gestation with Apgar scores of 9 and 9. By examination he seemed to be a healthy 36-week infant with a birth weight of 6 pounds. He progressed satisfactorily and was discharged to home 2 days later.At 29 days of age, baby Z was brought to the local hospital for evaluation of frequent cough and occasional vomiting, which had started the previous day. Physical examination at that time revealed a rectal temperature of 98.2°F, a pulse of 160, and respirations of 32. A chest radiograph showed no evidence of active cardiac or pulmonary pathology and the infant was diagnosed with an upper respiratory infection. Baby Z was discharged to home with instructions to treat with Triaminic syrup (Sandoz Consumer, East Hanover, NJ) and Pedialyte (Ross Laboratories, Columbus, OH).The baby did not improve over the course of the day and returned to the hospital emergency department later that afternoon. Physical examination revealed a temperature of 97°F, a pulse of 160, and respirations of 28. The chest was clear, the heart was in normal sinus rhythm, and the abdomen was soft. The assessment at this time was a viral tracheitis. The patient was discharged to home with instructions to take 1 mL Novahistine DH (SmithKline Beecham Pharmaceuticals, Pittsburgh, PA) every 6 hours for 3 days (Novahistine DH contains 2 mg of codeine per milliliter, and in this infant, the dose would have been .63 mg/kg), to discontinue the Triaminic medication, and to see the pediatrician in 2 days.At 8 pm the baby was given a 1-mL dose of oral Novahistine DH. At 2 am on the next day, a second 1-mL dose was given. At 3 am, the baby seemed to be in no distress according to the mother. At 4 am, the mother noted that the baby was unusually quiet and when she checked, the baby was not breathing. An ambulance was called, and the baby was transported to the hospital, where resuscitative efforts continued in the emergency department. Despite lifesaving measures, the patient died. Autopsy and Toxicology ResultsNotable findings at autopsy included severe bronchitis/bronchiolitis and mild bilateral pulmonary congestion.Codeine and metabolites in postmortem samples of blood, urine, and liver extract were identified and quantitated by gas chromatography, mass spectrometry.1 Codeine is metabolized by several mechanisms (discussed below), and the metabolites can...

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Pharmacokinetics and metabolism of codeine in humans

Cited by 98 publications

References 32 publications

Slow Delayed Rectifier Potassium Current Blockade Contributes Importantly to Drug-Induced Long QT Syndrome

Slow Delayed Rectifier Potassium Current Blockade Contributes Importantly to Drug-Induced Long QT Syndrome

CYP2D6 in the Metabolism of Opioids for Mild to Moderate Pain

Codeine Intoxication in the Neonate

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