Codeine pharmacokinetics

Hull JH, Findlay JWA, Rogers JF, Welch R Butz RF, Bustrack JA. An evaluation of tiie effects of smoking on codeine pharmacokinetics and bioavailability in normal human volunteers. Drug Intell Clin Pharm(m2) 16, 849-54. 

Pharmacokinetics Variably absorbed from the GI tract. Protein binding low. Metabolized in liver. Primarily excreted in urine as morphineglucuronide con j ugates and unchanged drug—morphine, codeine, papaverine, etc. Unknown if removed by hemodialysis. Half-life 2-3 hr. 

Pharmacokinetic properties Codeine (Sindrup and Brosen, 1995) has a good oral bioavailability. The compound is extensively metabolized by O- and N-demethylation followed by glucuronidation. The main metabolites are norcodeine, morphine and hydrocodeine and their glucuronides. There are indications (Yue et al., 1997), that the analgesic effect is reduced in persons with low CYP2D6 activity (poor metabolizers). 

Pharmacokinetic properties Like codeine, dihydrocodeine is metabolized by CYP2D6 yielding the active metabolite dihydromorphine (Ammon et al., 1999). N-Demethylation... 

Pharmacokinetic properties Ethylmorphine (Aasmundstad et al., 1995) has a reasonable oral bioavailability. Like codeine, it is metabolized by O- and N-desalkylation, leading to nor-ethylmorphine, morphine, nor-morphine, and the respective glucuronides. 

Members of the group of natural, semisynthetic, or synthetic alkaloid compounds prepared from opium are referred to as opioids. This group includes natural compounds usually denoted opiates, such as morphine and codeine, and the synthetic and semi synthetic compounds such as oxycodone, buprenorphine, fentanyl, methadone, and tramadol. The pharmacological effects and pharmacokinetic parameters of these drugs share many common characteristics and are illustrated with the prototypic drug in this class, morphine. 

Yue QY, Hasselstrom J, Svensson JO, Sawe J. Pharmacokinetics of codeine and its metabolites in Caucasian healthy volunteers comparisons between extensive and poor hydroxylators of debrisoquine. Br J Clin Pharmacol 1991 31 635-642. 

Kirchheiner J, Schmidt H, Tzvetkov M, Keulen J (2007) LotschJ, Roots I, Brockmoller J. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J 7(4) 257-265... 

This chapter concentrates on some drug choices in acute rather than chronic pain, but the same principles can be used to determine the appropriateness of other types of analgesic. The drugs considered in this section are paracetamol, non-steroidal anti-inflammatories (NSAIDs specifically diclofenac, ibuprofen, indometacin, naproxen, sulindac and tenoxicam) and opioids (codeine, dihydrocodeine, morphine, pethidine and tramadol). Unless otherwise stated, all pharmacokinetic data originate from standard reference sources [1-5] and apply to adults only. 

There is a scarcity of information regarding use of codeine, dihydrocodeine and tramadol in patients with liver impairment. On the basis of pharmacokinetic properties, dihydrocodeine may be preferred over codeine. Owing to a lack of information and the potentially detrimental characteristics of tramadol, other opioids should be used in preference if possible. 

Pharmacokinetics of codeine in cirrhotic patients are currently unknown. 

Poulsen L, Brosen K, Arendt-Nielsen L, Gram LF, Elbaek K, Sindrup SH. Codeine and morphine in extensive and poor metabolizers of sparteine pharmacokinetics, analgesic effects and side effects. Eur. J. Clin. Pharmacol. 1996 51 289-295. 

Lafolie P, Beck O, Lin Z, Albertoni F, Boreus L. Urine and plasma pharmacokinetics of codeine in healthy volunteers implications for drugs-of-abuse testing. J Anal Toxicol 1996 20 541-6. 

A number of drugs of abuse are known substrates (e.g., codeine, hydrocodone, p-methoxyamphetamine, amphetamine) or inhibitors (e g., (-)-cocaine, pentazocine) of CYP2D6. For some of these drugs, the pharmacokinetic differences due to the polymorphism will be so profound that they are likely to exceed pharmacodynamic sources of variation in response. For other drugs (e.g., hydrocodone to hydromorphone, codeine to morphine, oxycodone to oxymorphone), CYP2D6 may not contribute importantly to the overall clearance of the drug, but may catalyze the formation of highly active metabolites. 

Band, C.J. Band, P.R. Deschamps, M. Besner, J.-G. Goldman, A.J. Human pharmacokinetic study of immediate-release (codeine phosphate) and sustained-release (codeine contin) codeine. J.Clin. Pharmacol., 1994, 34, 938-943 [electrochemical detection SPE plasma ethylmorphine (IS)] Papadoyannis, I. Zotou, A. Samanidou, V. Theodoridis, G. Zougrou, F. Comparative study of different solid-phase extraction cartric es in the simultaneous RP-HPLC analysis of morphine and codeine in biological fluids. J.Liq.Chromatogn, 1993,16, 3017—3040 [simultaneous caffeine, morphine, quinine, strychnine SPE urine plasma LOD 10-20 ng/mL]... 

Double-blind studies in a large number of professional army drivers found that 50 mg of codeine and alcohol 0.5 g/kg, both alone and together, impaired their ability to drive safely on a static driving simulator. The number of collisions , neglected instructions and the times they drove off the road were increased. Alcohol does not appear to affect the pharmacokinetics of codeine. See also, controlled-release opioids, below. 

Bodd E, Beylich KM, Christophersen AS, Morland J. Oral administration of codeine in the presence of ethanol a pharmacokinetic study in man. Pharmacol Toocicol (1987) 61, 297-300. 

Amistrong AC, Cozza KL. Pharmacokinetic drug interactions of morphine, codeine, and their derivatives theory and clinical reality. Part I. Psychosomatics(200y) 44,167-71. 

Dayer P, Desmeules J, Stribemi R. In vitro forecasting of drugs that may interfere with codeine bioactivation, Eur J Drug Metab Pharmacokinet ( 992) 17,115-20. 

Ketoprofen reduced morphine-associated respiratory depression, and did not alter morphine pharmacokinetics. Similarly, diclofenac did not alter morphine pharmacokinetics in one study. Improved pain relief and reduced adverse effects have been found when morphine was given with lomoxicam, ketoprofen, or ketorolac. However, in another, diclofenac slightly increased respiratory depression despite reducing morphine use, possibly because of persistent levels of an active metabolite of morphine. Diclofenac did not affect the pharmacokinetics or analgesic effects of codeine in healthy subjects. Intramuscular diclofenac did not affect the pharmacokinetics of methadone solution in cancer patients. Ibuprofen did not appear to interact... 

A single 50-mg dose of diclofenac sodium did not have an important effect on the pharmacokinetics of a single 100-mg dose of codeine phosphate in a placebo-controlled crossover study in 12 healthy subjects. There was no effect on the metabolic clearance of morphine, and only a slight (about 5% to 10%) increase in the levels of glucuronide metabolites. In addition, diclofenac did not alter the analgesic effects of codeine as assessed in a cold pressor test (a test in which opioids, but not NSAIDs, are effective). ... 

Laneury JP, Duchene P, Hirt P, Delarue A, Gleizes S, HouinG, MolinierP. Comparative bi-oavailabilily study of codeine and ibuprofen after administration of the two products alone or in association to 24 healthy volunteers. EurJ Drug Metab Pharmacokinet. (1998) 23,185-9. 

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