BilZ0r
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Many opioids are prodrugs in one way or another. I can never remeber which ones are, so I made this simple review as a reference. (Wasn't the simple actually, took me all day)
Fig 1. shows the Michaelis-Menten kinetics of the formation of the reported inactive metabolite (the top of one) and the reported active metabolite (bottom). You can see that CYP2D6 mediates the formation of all the active metabolites, and CYP3A4 the inactive metabolites. You can see that the CYP2D6 is the high affinity site (with the exception of codeine), but that the velocity of the CYP3A4 mediated reaction is faster (because CYP3A4 makes up the huge majority of liver cytochromes).
Figure 2 shows us the peak plasma concentration reached by opioids and their reportidly active metabolites. You can see that the concentration of the "active metabolites" is generally 50-100x lower than the parent compound, with the exception of hydrocodone, which is only 5 times lower.
Figure 3 shows us the great increase in potency shown by all the metabolites, with the exception of oxymorphone.
For these results we can probably make assumptions on which drugs have active metabolites, by comparing the affinity of the drug and its metabolites for the µ-opioid receptor, and the peak plasma concentration they reach.
Oxycodone is almost certainly the active species, as its metabolite, oxymorphone only reaches a plasma concentration of >1nM, while it's affinity for the mu-opioid receptor is over 20 times that. This is supported by the fact that inhibiting CYP2D6 does not effect the physiological effects of Oxycodone [13].
Dihydrocodeine looks like its actions will be mediated by both the parent compound and the metabolite, as both compounds reach plasma concentrations very similar to the µ-opioid receptor affinity. The only clinical study investigating this question showed that CYP2D6 poor metabolizer (PMs) produced no dihydromorphine after dihydrocodeine, but their pupil diamter or pain theshold was no different than normal people, indicated that active metabolites play little role in dihydrocodeines action[14]. This however is not the best experiment, and intra-subject, enzyme inhibition experiment would be more conlusive
Codeine is definatly a pro-drug. Although the concentration of codeine gets close to its affinity for the mu-opioid receptor, its metabolites, morphine and morphine-6-glucuronide get well above their affinity. This assertion is supported by the fact that CYP2D6 inhibition decreases the codeine induced "high"[15].
Finally, hydrocodone does not look to be a prodrug. Even though hydromorphone's peak plasma concentration of gets well above its µ-opioid receptor affinity, so does hydrocodone, meaning that metabolism is not needed for its effects. This is supported by the result that physiological and subjective measures of opioid action induced by oral hydrocodone dosage were not effected by CYP2D6 inhibtion[16].
References:
1. Drug Metab Dispos. 2004 Apr;32(4):447-54.
Quantitative contribution of CYP2D6 and CYP3A to oxycodone metabolism in human liver and intestinal microsomes.
Lalovic B, Phillips B, Risler LL, Howald W, Shen DD.
2. Br J Clin Pharmacol. 1997 Dec;44(6):549-55.
Characterization of the human cytochrome P450 enzymes involved in the metabolism of dihydrocodeine.
Kirkwood LC, Nation RL, Somogyi AA
3. Eur J Clin Pharmacol. 1997;52(1):41-7.
Different effects of inhibitors on the O- and N-demethylation of codeine in human liver microsomes.
Yue QY, Sawe J
4. Br J Clin Pharmacol. 2004 Mar;57(3):287-97.
CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes.
Hutchinson MR, Menelaou A, Foster DJ, Coller JK, Somogyi AA.
5. Life Sci. 1999;64(22):2011-20.
Opioid binding profiles of new hydrazone, oxime, carbazone and semicarbazone derivatives of 14-alkoxymorphinans.
Monory K, Greiner E, Sartania N, Sallai L, Pouille Y, Schmidhammer H, Hanoune J, Borsodi A.
6. J Med Chem. 2001 Mar 15;44(6):857-62.
Investigation of the selectivity of oxymorphone- and naltrexone-derived ligands via site-directed mutagenesis of opioid receptors: exploring the "address" recognition locus.
Metzger TG, Paterlini MG, Ferguson DM, Portoghese PS.
7. Pharmacol Toxicol. 2002 Aug;91(2):57-63.
Affinities of dihydrocodeine and its metabolites to opioid receptors.
Schmidt H, Vormfelde S, Klinder K, Gundert-Remy U, Gleiter CH, Skopp G, Aderjan R, Fuhr U.
8. Life Sci. 1991;48(22):2165-71.
Mu receptor binding of some commonly used opioids and their metabolites.
Chen ZR, Irvine RJ, Somogyi AA, Bochner F.
9. Br J Clin Pharmacol. 1999 Sep;48(3):317-22.
Pharmacokinetics of dihydrocodeine and its active metabolite after single and multiple oral dosing.
Ammon S, Hofmann U, Griese EU, Gugeler N, Mikus G.
10. Clin Pharmacol Ther. 1998 Dec;64(6):603-11.
Effects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone.
Heiskanen T, Olkkola KT, Kalso E.
11. Clin Pharmacol Ther. 1993 Nov;54(5):463-72.
CYP2D6 phenotype determines the metabolic conversion of hydrocodone to hydromorphone.
Otton SV, Schadel M, Cheung SW, Kaplan HL, Busto UE, Sellers EM.
12. J Pharmacol Exp Ther. 1999 Jul;290(1):413-22.
Impact of ethnic origin and quinidine coadministration on codeine's disposition and pharmacodynamic effects.
Caraco Y, Sheller J, Wood AJ.
13. Clin Pharmacol Ther. 1998 Dec;64(6):603-11.
Effects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone.
Heiskanen T, Olkkola KT, Kalso E.
14. Int J Clin Pharmacol Ther. 2003 Mar;41(3):95-106.
The role of active metabolites in dihydrocodeine effects.
Schmidt H, Vormfelde SV, Walchner-Bonjean M, Klinder K, Freudenthaler S, Gleiter CH, Gundert-Remy U, Skopp G, Aderjan R, Fuhr U.
15. J Clin Psychopharmacol. 2000 Aug;20(4):435-44.
Inhibition of cytochrome P450 2D6 modifies codeine abuse liability.
Kathiramalainathan K, Kaplan HL, Romach MK, Busto UE, Li NY, Sawe J, Tyndale RF, Sellers EM.
16. J Pharmacol Exp Ther. 1997 Apr;281(1):103-8.
Inhibition of cytochrome P450 2D6 metabolism of hydrocodone to hydromorphone does not importantly affect abuse liability.
Kaplan HL, Busto UE, Baylon GJ, Cheung SW, Otton SV, Somer G, Sellers EM.
Fig 1. shows the Michaelis-Menten kinetics of the formation of the reported inactive metabolite (the top of one) and the reported active metabolite (bottom). You can see that CYP2D6 mediates the formation of all the active metabolites, and CYP3A4 the inactive metabolites. You can see that the CYP2D6 is the high affinity site (with the exception of codeine), but that the velocity of the CYP3A4 mediated reaction is faster (because CYP3A4 makes up the huge majority of liver cytochromes).
Fig 1. Kinetics of the formation of opioid metabolites
Figure 2 shows us the peak plasma concentration reached by opioids and their reportidly active metabolites. You can see that the concentration of the "active metabolites" is generally 50-100x lower than the parent compound, with the exception of hydrocodone, which is only 5 times lower.
Fig 2. Peak plasma concentration of various opioids and their reportidly active metabolites after oral dosage in humans
Figure 3 shows us the great increase in potency shown by all the metabolites, with the exception of oxymorphone.
Fig 3. Affinity of the various opioids and metabolites for the µ-opioid receptor (generally tested by displacement of 3H-DAMGO)
For these results we can probably make assumptions on which drugs have active metabolites, by comparing the affinity of the drug and its metabolites for the µ-opioid receptor, and the peak plasma concentration they reach.
Oxycodone is almost certainly the active species, as its metabolite, oxymorphone only reaches a plasma concentration of >1nM, while it's affinity for the mu-opioid receptor is over 20 times that. This is supported by the fact that inhibiting CYP2D6 does not effect the physiological effects of Oxycodone [13].
Dihydrocodeine looks like its actions will be mediated by both the parent compound and the metabolite, as both compounds reach plasma concentrations very similar to the µ-opioid receptor affinity. The only clinical study investigating this question showed that CYP2D6 poor metabolizer (PMs) produced no dihydromorphine after dihydrocodeine, but their pupil diamter or pain theshold was no different than normal people, indicated that active metabolites play little role in dihydrocodeines action[14]. This however is not the best experiment, and intra-subject, enzyme inhibition experiment would be more conlusive
Codeine is definatly a pro-drug. Although the concentration of codeine gets close to its affinity for the mu-opioid receptor, its metabolites, morphine and morphine-6-glucuronide get well above their affinity. This assertion is supported by the fact that CYP2D6 inhibition decreases the codeine induced "high"[15].
Finally, hydrocodone does not look to be a prodrug. Even though hydromorphone's peak plasma concentration of gets well above its µ-opioid receptor affinity, so does hydrocodone, meaning that metabolism is not needed for its effects. This is supported by the result that physiological and subjective measures of opioid action induced by oral hydrocodone dosage were not effected by CYP2D6 inhibtion[16].
References:
1. Drug Metab Dispos. 2004 Apr;32(4):447-54.
Quantitative contribution of CYP2D6 and CYP3A to oxycodone metabolism in human liver and intestinal microsomes.
Lalovic B, Phillips B, Risler LL, Howald W, Shen DD.
2. Br J Clin Pharmacol. 1997 Dec;44(6):549-55.
Characterization of the human cytochrome P450 enzymes involved in the metabolism of dihydrocodeine.
Kirkwood LC, Nation RL, Somogyi AA
3. Eur J Clin Pharmacol. 1997;52(1):41-7.
Different effects of inhibitors on the O- and N-demethylation of codeine in human liver microsomes.
Yue QY, Sawe J
4. Br J Clin Pharmacol. 2004 Mar;57(3):287-97.
CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes.
Hutchinson MR, Menelaou A, Foster DJ, Coller JK, Somogyi AA.
5. Life Sci. 1999;64(22):2011-20.
Opioid binding profiles of new hydrazone, oxime, carbazone and semicarbazone derivatives of 14-alkoxymorphinans.
Monory K, Greiner E, Sartania N, Sallai L, Pouille Y, Schmidhammer H, Hanoune J, Borsodi A.
6. J Med Chem. 2001 Mar 15;44(6):857-62.
Investigation of the selectivity of oxymorphone- and naltrexone-derived ligands via site-directed mutagenesis of opioid receptors: exploring the "address" recognition locus.
Metzger TG, Paterlini MG, Ferguson DM, Portoghese PS.
7. Pharmacol Toxicol. 2002 Aug;91(2):57-63.
Affinities of dihydrocodeine and its metabolites to opioid receptors.
Schmidt H, Vormfelde S, Klinder K, Gundert-Remy U, Gleiter CH, Skopp G, Aderjan R, Fuhr U.
8. Life Sci. 1991;48(22):2165-71.
Mu receptor binding of some commonly used opioids and their metabolites.
Chen ZR, Irvine RJ, Somogyi AA, Bochner F.
9. Br J Clin Pharmacol. 1999 Sep;48(3):317-22.
Pharmacokinetics of dihydrocodeine and its active metabolite after single and multiple oral dosing.
Ammon S, Hofmann U, Griese EU, Gugeler N, Mikus G.
10. Clin Pharmacol Ther. 1998 Dec;64(6):603-11.
Effects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone.
Heiskanen T, Olkkola KT, Kalso E.
11. Clin Pharmacol Ther. 1993 Nov;54(5):463-72.
CYP2D6 phenotype determines the metabolic conversion of hydrocodone to hydromorphone.
Otton SV, Schadel M, Cheung SW, Kaplan HL, Busto UE, Sellers EM.
12. J Pharmacol Exp Ther. 1999 Jul;290(1):413-22.
Impact of ethnic origin and quinidine coadministration on codeine's disposition and pharmacodynamic effects.
Caraco Y, Sheller J, Wood AJ.
13. Clin Pharmacol Ther. 1998 Dec;64(6):603-11.
Effects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone.
Heiskanen T, Olkkola KT, Kalso E.
14. Int J Clin Pharmacol Ther. 2003 Mar;41(3):95-106.
The role of active metabolites in dihydrocodeine effects.
Schmidt H, Vormfelde SV, Walchner-Bonjean M, Klinder K, Freudenthaler S, Gleiter CH, Gundert-Remy U, Skopp G, Aderjan R, Fuhr U.
15. J Clin Psychopharmacol. 2000 Aug;20(4):435-44.
Inhibition of cytochrome P450 2D6 modifies codeine abuse liability.
Kathiramalainathan K, Kaplan HL, Romach MK, Busto UE, Li NY, Sawe J, Tyndale RF, Sellers EM.
16. J Pharmacol Exp Ther. 1997 Apr;281(1):103-8.
Inhibition of cytochrome P450 2D6 metabolism of hydrocodone to hydromorphone does not importantly affect abuse liability.
Kaplan HL, Busto UE, Baylon GJ, Cheung SW, Otton SV, Somer G, Sellers EM.
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![:\](https://bluelight.org/xf/BL_Images/Orig_Emoji/wrygrin.gif "wry grin :\")