Journal of Analytical Toxicology 2015;39:81 –82 doi:10.1093/jat/bku111 Advance Access publication October 6, 2014
Letter to the Editor
Urine Drug Testing for Oxycodone and Its Metabolites as a Tool for Drug–Drug Interactions? A recent article by Elder et al. (1) used urinary concentrations of oxycodone, oxymorphone and noroxycodone from a large patient sample collected for routine drug monitoring purposes. The two aims were the identification of factors contributing to the known drug testing variability and the potential monitoring of clinically significant drug –drug interactions. Unfortunately, in only 49% of the urine specimens, noroxycodone was detected which was already addressed by DePriest et al. (2) showing the discrepancy to the current literature data where urinary noroxycodone prevalence was always above 90% questioning the validity of the study results. In reply to this letter, Elder et al. (3) admitted an ‘error’ at the start of the analysis and they present three updated tables with different results of the mole fractions. This leaves a number of open questions for the original publication. This large discrepancy between the current knowledge of high prevalence of urinary noroxycodone published (4 –6), and the study findings should have triggered a discussion about the reasons as well as a re-evaluation of the data. This was done only as a reaction to the letter by DePriest et al. (2). With the new data provided (3), the prevalence is now in the previously known range. The second aim of the investigation was the monitoring of clinically significant drug –drug interactions. With the new data analysis, there are numerous changes (listed in their Table III) in the alterations of the mole fractions based on the physician-reported CYP2D6 and CYP3A4 substrate and/or inhibitor use, which is not even discussed. The authors acknowledge in their reply (3) the limitation of physician-reported medication. However, in the exclusion criteria of the dataset it is mentioned that 35 subjects have been
excluded due to the use of CYP2D6 inducers (1). So far, no drug has been identified to be able to induce the polymorphic CYP2D6 enzyme in vitro and in vivo (7). This supports even more the uncertainty in the method of obtaining the physicianreported medication and hence the validity of the results. Understanding the metabolism of a drug and the enzymes mediating this is a key point when interpreting urinary concentrations and mole fractions especially for the assessment of drug – drug interactions. For the assessment of CYP-mediated metabolic interactions, three metabolites are important; noroxycodone, oxymorphone, and noroxymorphone, the latter one is formed as a secondary metabolite (Figure 1). The metabolic pattern after oxycodone administration to humans has been studied thoroughly by Lalovic et al. (8). They showed that 72 + 19% of a given oxycodone dose is excreted in urine over 48 h with oxycodone accounting for 8.9% only (8). Noroxycodone is the major urinary metabolite with 23.1% of the dose followed by the secondary metabolite noroxymorphone with 14.2%, and oxymorphone (mainly conjugated) with 10.7% (8). The two-step formation of noroxymorphone always involves CYP2D6 and CYP3A4 either in the first or the second step. Therefore, inhibition of CYP3A4 results in decreased formation of noroxycodone from oxycodone and also decreased formation of noroxymorphone from oxymorphone. Inhibition of CYP2D6 will reduce the formation of oxymorphone from oxycodone as well as noroxymorphone from noroxycodone (Figure 1). Unfortunately, Elder et al. quantified the primary metabolites only (1, 3). This is a very complex situation, which has also been reported for dextromethorphan that has very similar metabolic pathways and enzymes involved (9). It is therefore not possible to use urinary mole
Figure 1. CYP-mediated metabolic pathways of oxycodone and the proposed effects of single and dual enzyme inhibition on urinary excretion.
# The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
Letter to the Editor
fractions from drugs like oxycodone or dextromethorphan with its complex metabolism (several enzymes and primary and secondary metabolic steps involved) to monitor clinically significant drug–drug interactions.
References 1. Elder, N.M., Atayee, R.S., Best, B.M., Ma, J.D. (2014) Observations of urinary oxycodone and metabolite distributions in pain patients. Journal of Analytical Toxicology, 38, 129–134. 2. DePriest, A.Z., Puet, B.L., Heltsley, R., Robert, T., Black, D.L. (2014) Uncertainty in assessing impact of drug – drug interactions on oxycodone metabolite patterns. Journal of Analytical Toxicology, 38, 462. 3. Elder, N.M., Atayee, R.S., Best, B.M., Ma, J.D. (2014) Authors’ reply. Journal of Analytical Toxicology, 38, 463. 4. Heltsley, R., Zichterman, A., Black, D.L., Cawthon, B., Robert, T., Moser, F. et al. (2010) Urine drug testing of chronic pain patients. II. Prevalence patterns of prescription opiates and metabolites. Journal of Analytical Toxicology, 34, 32 –38. 5. Cone, E.J., Zichterman, A., Heltsley, R., Black, D.L., Cawthon, B., Robert, T. et al. (2010) Urine testing for norcodeine, norhydrocodone, and noroxycodone facilitates interpretation and reduces false negatives. Forensic Science International, 198, 58 –61.
6. Cone, E.J., Heltsley, R., Black, D.L., Mitchell, J.M., Lodico, C.P., Flegel, R.R. (2013) Prescription opioids. I. Metabolism and excretion patterns of oxycodone in urine following controlled single dose administration. Journal of Analytical Toxicology, 37, 255– 264. 7. US Food and Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers 2011. http://www.fda.gov/drugs/developmentapprovalprocess/ developmentresources/druginteractionslabeling/ucm093664.htm (assessed July 21, 2014). 8. Lalovic, B., Kharasch, E., Hoffer, C., Risler, L., Liu-Chen, L.Y., Shen, D.D. (2006) Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites. Clinical Pharmacology & Therapeutics, 79, 461– 479. 9. Capon, D.A., Bochner, F., Kerry, N., Mikus, G., Danz, C., Somogyi, A.A. (1996) The influence of CYP2D6 polymorphism and quinidine on the disposition and antitussive effect of dextromethorphan in humans. Clinical Pharmacology & Therapeutics, 60, 295– 307.
Gerd Mikus* Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany *Author to whom correspondence should be addressed. Email: [email protected]
Letter to the Editor
Urine Drug Testing for Oxycodone and Its Metabolites as a Tool for Drug–Drug Interactions? A recent article by Elder et al. (1) used urinary concentrations of oxycodone, oxymorphone and noroxycodone from a large patient sample collected for routine drug monitoring purposes. The two aims were the identification of factors contributing to the known drug testing variability and the potential monitoring of clinically significant drug –drug interactions. Unfortunately, in only 49% of the urine specimens, noroxycodone was detected which was already addressed by DePriest et al. (2) showing the discrepancy to the current literature data where urinary noroxycodone prevalence was always above 90% questioning the validity of the study results. In reply to this letter, Elder et al. (3) admitted an ‘error’ at the start of the analysis and they present three updated tables with different results of the mole fractions. This leaves a number of open questions for the original publication. This large discrepancy between the current knowledge of high prevalence of urinary noroxycodone published (4 –6), and the study findings should have triggered a discussion about the reasons as well as a re-evaluation of the data. This was done only as a reaction to the letter by DePriest et al. (2). With the new data provided (3), the prevalence is now in the previously known range. The second aim of the investigation was the monitoring of clinically significant drug –drug interactions. With the new data analysis, there are numerous changes (listed in their Table III) in the alterations of the mole fractions based on the physician-reported CYP2D6 and CYP3A4 substrate and/or inhibitor use, which is not even discussed. The authors acknowledge in their reply (3) the limitation of physician-reported medication. However, in the exclusion criteria of the dataset it is mentioned that 35 subjects have been
excluded due to the use of CYP2D6 inducers (1). So far, no drug has been identified to be able to induce the polymorphic CYP2D6 enzyme in vitro and in vivo (7). This supports even more the uncertainty in the method of obtaining the physicianreported medication and hence the validity of the results. Understanding the metabolism of a drug and the enzymes mediating this is a key point when interpreting urinary concentrations and mole fractions especially for the assessment of drug – drug interactions. For the assessment of CYP-mediated metabolic interactions, three metabolites are important; noroxycodone, oxymorphone, and noroxymorphone, the latter one is formed as a secondary metabolite (Figure 1). The metabolic pattern after oxycodone administration to humans has been studied thoroughly by Lalovic et al. (8). They showed that 72 + 19% of a given oxycodone dose is excreted in urine over 48 h with oxycodone accounting for 8.9% only (8). Noroxycodone is the major urinary metabolite with 23.1% of the dose followed by the secondary metabolite noroxymorphone with 14.2%, and oxymorphone (mainly conjugated) with 10.7% (8). The two-step formation of noroxymorphone always involves CYP2D6 and CYP3A4 either in the first or the second step. Therefore, inhibition of CYP3A4 results in decreased formation of noroxycodone from oxycodone and also decreased formation of noroxymorphone from oxymorphone. Inhibition of CYP2D6 will reduce the formation of oxymorphone from oxycodone as well as noroxymorphone from noroxycodone (Figure 1). Unfortunately, Elder et al. quantified the primary metabolites only (1, 3). This is a very complex situation, which has also been reported for dextromethorphan that has very similar metabolic pathways and enzymes involved (9). It is therefore not possible to use urinary mole
Figure 1. CYP-mediated metabolic pathways of oxycodone and the proposed effects of single and dual enzyme inhibition on urinary excretion.
# The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
Letter to the Editor
fractions from drugs like oxycodone or dextromethorphan with its complex metabolism (several enzymes and primary and secondary metabolic steps involved) to monitor clinically significant drug–drug interactions.
References 1. Elder, N.M., Atayee, R.S., Best, B.M., Ma, J.D. (2014) Observations of urinary oxycodone and metabolite distributions in pain patients. Journal of Analytical Toxicology, 38, 129–134. 2. DePriest, A.Z., Puet, B.L., Heltsley, R., Robert, T., Black, D.L. (2014) Uncertainty in assessing impact of drug – drug interactions on oxycodone metabolite patterns. Journal of Analytical Toxicology, 38, 462. 3. Elder, N.M., Atayee, R.S., Best, B.M., Ma, J.D. (2014) Authors’ reply. Journal of Analytical Toxicology, 38, 463. 4. Heltsley, R., Zichterman, A., Black, D.L., Cawthon, B., Robert, T., Moser, F. et al. (2010) Urine drug testing of chronic pain patients. II. Prevalence patterns of prescription opiates and metabolites. Journal of Analytical Toxicology, 34, 32 –38. 5. Cone, E.J., Zichterman, A., Heltsley, R., Black, D.L., Cawthon, B., Robert, T. et al. (2010) Urine testing for norcodeine, norhydrocodone, and noroxycodone facilitates interpretation and reduces false negatives. Forensic Science International, 198, 58 –61.
6. Cone, E.J., Heltsley, R., Black, D.L., Mitchell, J.M., Lodico, C.P., Flegel, R.R. (2013) Prescription opioids. I. Metabolism and excretion patterns of oxycodone in urine following controlled single dose administration. Journal of Analytical Toxicology, 37, 255– 264. 7. US Food and Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers 2011. http://www.fda.gov/drugs/developmentapprovalprocess/ developmentresources/druginteractionslabeling/ucm093664.htm (assessed July 21, 2014). 8. Lalovic, B., Kharasch, E., Hoffer, C., Risler, L., Liu-Chen, L.Y., Shen, D.D. (2006) Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites. Clinical Pharmacology & Therapeutics, 79, 461– 479. 9. Capon, D.A., Bochner, F., Kerry, N., Mikus, G., Danz, C., Somogyi, A.A. (1996) The influence of CYP2D6 polymorphism and quinidine on the disposition and antitussive effect of dextromethorphan in humans. Clinical Pharmacology & Therapeutics, 60, 295– 307.
Gerd Mikus* Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany *Author to whom correspondence should be addressed. Email: [email protected]
