Journal of Analytical Toxicology 2015;39:80 doi:10.1093/jat/bku112 Advance Access publication October 6, 2014
Letter to the Editor
Response to Urine Drug Testing for Oxycodone and Its Metabolites as a Tool for Drug–Drug Interactions Mikus (1) provides discussion regarding a previously published article by Elder et al. (2) and a letter to the editor by the same authors stating an error in the original analysis resulting in a data reanalysis and revised results (3). Mikus (1) makes mention of the lack of discussion in the letter to the editor (3) regarding revised results of oxycodone, oxymorphone and noroxycodone mole fractions and physician-reported cytochrome P450 (CYP) 2D6 and CYP3A4/5 substrate and/or inhibitor use. We did not provide our interpretation of the revised results from these data as this was not a specific question asked by DePriest et al. (4). In the original analysis, mole fractions of oxycodone, oxymorphone and noroxycodone were 0.43, 0.33 and 0.51, respectively (2). In the revised analysis, mole fractions of oxycodone, oxymorphone and noroxycodone were 0.25, 0.23 and 0.51, respectively (3). Oxymorphone mole fractions decreased while noroxycodone mole fractions increased during concurrent administration of only a CYP2D6 substrate and only a CYP2D6 inhibitor. These results were consistent upon evaluation of concurrent administration of both a CYP2D6 substrate and a CYP2D6 inhibitor (3). Based on the metabolic pathway of oxycodone, these results are expected. Results during CYP3A4/5 substrate and inhibition use are mixed. We expected a decrease in noroxycodone mole fractions and an increase in oxymorphone mole fractions during CYP3A4/5 inhibition. Consistent with expectations, oxymorphone mole fractions increased. Surprisingly, noroxycodone mole fractions also increased (3). Our interpretation is that this result is to be interpreted with caution as this was not statistically significant and involved a low sample size (3). Based on the reanalysis and consistent with conclusions from the original paper (2), increased awareness of concurrent use of oxycodone and other medications that are metabolized by CYP2D6 and/or CYP3A4/5 are recommended. We make no conclusions or recommendations based on study findings that urine drug concentrations are a tool to evaluate drug – drug interactions. Rather, consistent with DePriest’s et al. letter (4), we agree that this is a topic of further study. Mikus (1) also questions the study design of excluding subjects (n ¼ 35) on CYP2D6 inducers with specific mention of no known in vitro and in vivo CYP2D6 inducers. We thank Mikus for citing an FDA website to support his statement of no known CYP2D6 inducers. In our analysis, we utilized a different resource that listed rifampin and dexamethasone as CYP2D6 inducers (4). In the same resource, rifampin was also listed as a CYP1A2, CYP2B6, CYP2C8 and CYP3A4/5 inducer (5). We acknowledge that there are sparse data to support these medications as CYP2D6 inducers. However, a healthy subject
phenotyping study evaluated the effects of rifampin on the simultaneous activities of CYP1A2, CYP2C19, CYP2D6 and CYP3A4 (6). After rifampin administration, time-dependent induction was observed for all evaluated drug-metabolizing enzymes (6). This included induction of CYP2D6 (6). All 35 subjects that were identified as being on a CYP2D6 inducer had physicianreported use of rifampin. We believe that removing subjects who were on CYP2D6 inducers, as well as CYP3A4/5 inducers, did not contribute to ‘uncertainty in the method’ but merely removed all known and possible CYP3A4/5 and CYP2D6 inducers from the data analysis. Mikus (1) goes on to further describe oxycodone metabolism and provides additional figures and citations. We provide similar information (as well as a similar figure) regarding multiple routes of oxycodone metabolism and metabolite formation (2).
References 1. Mikus, G. (2014) Urine drug testing for oxycodone and its metabolites as a tool for drug–drug interactions. Journal of Analytical Toxicology, In press. 2. 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. 3. Elder, N.M., Atayee, R.S., Best, B.M., Ma, J.D. (2014) Authors’ reply. Journal of Analytical Toxicology, 38, 463. 4. DePriest, A.Z., Puet, B.L., Heltsley, R., Cawthon, B., Robert, T., Black, D.L. (2014) Uncertainty in assessing the impact of drug– drug interactions on oxycodone metabolite patterns. Journal of Analytical Toxicology, 38, 462. 5. Indiana University. School of Medicine. Department of Clinical Pharmacology. P450 Drug Interaction Table. http://medicine.iupui. edu/clinpharm/ddis/table.aspx (accessed Aug 6, 2014). 6. Branch, R.A., Adedoyin, A., Frye, R.F., Wilson, J.W., Romkes, M. (2000) In vivo modulation of CYP enzymes by quinidine and rifampin. Clinical Pharmacology and Therapeutics, 68, 401– 411.
Natalie M. Elder1, Rabia S. Atayee1,2 , Brookie M. Best1,3 and Joseph D. Ma1,2,* 1 University of California, San Diego (UC San Diego), Skaggs School of Pharmacy & Pharmaceutical Sciences, La Jolla, CA, USA 2 Doris A. Howell Pain and Palliative Care Service, La Jolla, CA, USA 3 UC San Diego Department of Pediatrics, Rady Children’s Hospital, San Diego, CA, USA *Author to whom correspondence should be addressed. Email: [email protected]
# The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
Letter to the Editor
Response to Urine Drug Testing for Oxycodone and Its Metabolites as a Tool for Drug–Drug Interactions Mikus (1) provides discussion regarding a previously published article by Elder et al. (2) and a letter to the editor by the same authors stating an error in the original analysis resulting in a data reanalysis and revised results (3). Mikus (1) makes mention of the lack of discussion in the letter to the editor (3) regarding revised results of oxycodone, oxymorphone and noroxycodone mole fractions and physician-reported cytochrome P450 (CYP) 2D6 and CYP3A4/5 substrate and/or inhibitor use. We did not provide our interpretation of the revised results from these data as this was not a specific question asked by DePriest et al. (4). In the original analysis, mole fractions of oxycodone, oxymorphone and noroxycodone were 0.43, 0.33 and 0.51, respectively (2). In the revised analysis, mole fractions of oxycodone, oxymorphone and noroxycodone were 0.25, 0.23 and 0.51, respectively (3). Oxymorphone mole fractions decreased while noroxycodone mole fractions increased during concurrent administration of only a CYP2D6 substrate and only a CYP2D6 inhibitor. These results were consistent upon evaluation of concurrent administration of both a CYP2D6 substrate and a CYP2D6 inhibitor (3). Based on the metabolic pathway of oxycodone, these results are expected. Results during CYP3A4/5 substrate and inhibition use are mixed. We expected a decrease in noroxycodone mole fractions and an increase in oxymorphone mole fractions during CYP3A4/5 inhibition. Consistent with expectations, oxymorphone mole fractions increased. Surprisingly, noroxycodone mole fractions also increased (3). Our interpretation is that this result is to be interpreted with caution as this was not statistically significant and involved a low sample size (3). Based on the reanalysis and consistent with conclusions from the original paper (2), increased awareness of concurrent use of oxycodone and other medications that are metabolized by CYP2D6 and/or CYP3A4/5 are recommended. We make no conclusions or recommendations based on study findings that urine drug concentrations are a tool to evaluate drug – drug interactions. Rather, consistent with DePriest’s et al. letter (4), we agree that this is a topic of further study. Mikus (1) also questions the study design of excluding subjects (n ¼ 35) on CYP2D6 inducers with specific mention of no known in vitro and in vivo CYP2D6 inducers. We thank Mikus for citing an FDA website to support his statement of no known CYP2D6 inducers. In our analysis, we utilized a different resource that listed rifampin and dexamethasone as CYP2D6 inducers (4). In the same resource, rifampin was also listed as a CYP1A2, CYP2B6, CYP2C8 and CYP3A4/5 inducer (5). We acknowledge that there are sparse data to support these medications as CYP2D6 inducers. However, a healthy subject
phenotyping study evaluated the effects of rifampin on the simultaneous activities of CYP1A2, CYP2C19, CYP2D6 and CYP3A4 (6). After rifampin administration, time-dependent induction was observed for all evaluated drug-metabolizing enzymes (6). This included induction of CYP2D6 (6). All 35 subjects that were identified as being on a CYP2D6 inducer had physicianreported use of rifampin. We believe that removing subjects who were on CYP2D6 inducers, as well as CYP3A4/5 inducers, did not contribute to ‘uncertainty in the method’ but merely removed all known and possible CYP3A4/5 and CYP2D6 inducers from the data analysis. Mikus (1) goes on to further describe oxycodone metabolism and provides additional figures and citations. We provide similar information (as well as a similar figure) regarding multiple routes of oxycodone metabolism and metabolite formation (2).
References 1. Mikus, G. (2014) Urine drug testing for oxycodone and its metabolites as a tool for drug–drug interactions. Journal of Analytical Toxicology, In press. 2. 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. 3. Elder, N.M., Atayee, R.S., Best, B.M., Ma, J.D. (2014) Authors’ reply. Journal of Analytical Toxicology, 38, 463. 4. DePriest, A.Z., Puet, B.L., Heltsley, R., Cawthon, B., Robert, T., Black, D.L. (2014) Uncertainty in assessing the impact of drug– drug interactions on oxycodone metabolite patterns. Journal of Analytical Toxicology, 38, 462. 5. Indiana University. School of Medicine. Department of Clinical Pharmacology. P450 Drug Interaction Table. http://medicine.iupui. edu/clinpharm/ddis/table.aspx (accessed Aug 6, 2014). 6. Branch, R.A., Adedoyin, A., Frye, R.F., Wilson, J.W., Romkes, M. (2000) In vivo modulation of CYP enzymes by quinidine and rifampin. Clinical Pharmacology and Therapeutics, 68, 401– 411.
Natalie M. Elder1, Rabia S. Atayee1,2 , Brookie M. Best1,3 and Joseph D. Ma1,2,* 1 University of California, San Diego (UC San Diego), Skaggs School of Pharmacy & Pharmaceutical Sciences, La Jolla, CA, USA 2 Doris A. Howell Pain and Palliative Care Service, La Jolla, CA, USA 3 UC San Diego Department of Pediatrics, Rady Children’s Hospital, San Diego, CA, USA *Author to whom correspondence should be addressed. Email: [email protected]
# The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
