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Is saliva a valid substitute for plasma in pharmacokinetic studies of oxycodone and its metabolites in patients with cancer?

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Abstract

Purpose

Little is known about the pharmacokinetics (PKs) of oxycodone in patients with advanced cancer. There is considerable reluctance to subject these patients to non-essential tests including repeated venipuncture that has been necessary in PK studies to date. We investigated the possibility of using saliva sampling as a simple non-invasive test to investigate opioid PKs.

Methods

Patients with malignant disease receiving oral sustained release (SR) oxycodone at any dose were asked to provide saliva samples at the same time as blood samples. Samples were not taken within 6 h of a dose of immediate release oxycodone. Plasma and saliva oxycodone and metabolite concentrations were measured using HPLC coupled with tandem mass spectrometric detection.

Results

One hundred and thirty-nine paired plasma/saliva samples were collected from 43 cancer patients who had been taking SR oxycodone for more than 5 days at doses ranging from 10 to 600 mg/day (median 40 mg/day). Plasma concentrations of oxycodone and noroxycodone ranged from 1.0 to 256.0 and 0.9–269.4 μg/L, respectively. Salivary concentrations of oxycodone (range 0.93–3,620, mean 336 μg/L) were much higher than plasma concentrations (mean 38.2 μg/L). There was a poor correlation between concentrations of both oxycodone and noroxycodone in plasma and saliva over a range of times following dosing (r 2 = 0.4641 and 0.3891, respectively). No correlation was shown between salivary pH and oxycodone or noroxycodone concentrations. The majority of patients questioned chose saliva sampling over plasma sampling as the preferred method.

Conclusion

High levels of both oxycodone and its major metabolite are present in saliva, but this does not provide a valid substitute for plasma when monitoring oxycodone levels for PK studies or therapeutic monitoring.

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References

  1. Mullangi R, Agrawal S, Srinivas N (2009) Measurement of xenobiotics in saliva: is saliva an attractive alternative matrix? Case studies and analytical perspectives. Biomed Chromatogr 23:3–25

    Article  PubMed  CAS  Google Scholar 

  2. Michael C, Teichert J, Preiss R (2008) Determination of voriconazole in human plasma and saliva using high performance liquid chromatography with fluorescence detection. J Chromatogr B Analyt Technol Biomed Life Sci 865:74–80

    Article  PubMed  CAS  Google Scholar 

  3. Gallagher P, Leitch M, Massey A, McAllister-Williams R, Young A (2006) Assessing cortisol and dehydroepiandrosterone (DHEA) in saliva: effect of collection method. J Psychopharmacol 20:643–649

    Article  PubMed  CAS  Google Scholar 

  4. Poujol S, Bressolle F, Duffour J, Abderrahim AG, Astre C, Ychou M, Pinguet F (2006) Pharmacokinetics and pharmacodynamics of irinotecan and its metabolites from plasma and saliva data in patients with metastatic digestive cancer receiving Folfiri regimen. Cancer Chemother Pharmacol 58:292–305

    Article  PubMed  CAS  Google Scholar 

  5. Voultsios A, Kennaway D, Dawson D (1997) Salivary melatonin as a circadian phase marker: validation and comparison to plasma melatonin. J Biol Rhythms 12:457–466

    PubMed  CAS  Google Scholar 

  6. Ruiz ME, Conforti P, Fagiolino P, Volonté MG (2010) The use of saliva as a biological fluid in relative bioavailability studies: comparison and correlation with plasma results. Biopharm Drug Dispos 31:476–485

    Article  PubMed  CAS  Google Scholar 

  7. Gubala W, Zuba D (2003) Gender differences in the pharmacokinetics of ethanol in saliva and blood after oral ingestion. Pol J Pharmacol 55:639–644

    PubMed  Google Scholar 

  8. Gorodischer R, Koren G (1992) Salivary excretion of drugs in children: theoretical and practical issues in therapeutic drug monitoring. Dev Pharmacol Ther 9:161–177

    Google Scholar 

  9. Gorodischer R, Burtin P et al (1997) Is saliva suitable for therapeutic monitoring of anticonvulsants in children: an evaluation in the routine clinical setting. Ther Drug Monit 19(6):637–642

    Article  PubMed  CAS  Google Scholar 

  10. Gandia P, Bareille M, Saivin S, Pavy Le-Traon A, Lavit M, Guell A, Houin G (2003) Influence of simulated weightlessness on the oral pharmacokinetics of acetaminophen as a gastric emptying probe in man: a plasma and a saliva study. J Clin Pharmacol 43:1235–1243

    Article  PubMed  CAS  Google Scholar 

  11. Ritschel WA, Parab PV, Denson DD, Coyle DE, Gregg RV (1987) Absolute bioavailability of hydromorphone after peroral and rectal administration in humans: saliva/plasma ratio and clinical effects. J Clin Pharmacol 27:647–653

    PubMed  CAS  Google Scholar 

  12. Davis M, Varga J, Dickerson D, Walsh D, LeGrand SB, Lagman R (2003) Normal-release and controlled-release oxycodone: pharmacokinetics, pharmacodynamics, and controversy. Support Care Cancer 11:84–92

    PubMed  Google Scholar 

  13. Grönlund J, Saari TI, Hagelberg NM, Neuvonen PJ, Olkkola KT, Laine K (2010) Exposure to oral oxycodone is increased by concomitant inhibition of CYP2D6 and 3A4 pathways, but not by inhibition of CYP2D6 alone. Br J Clin Pharmacol 70:78–87

    Article  PubMed  Google Scholar 

  14. Glare P, Davis M (2009) Oxycodone. In: Davis M, Glare P, Hardy JR (eds) Opioids in cancer pain, 2nd edn. Oxford University Press, Oxford, UK

    Google Scholar 

  15. Lalovic B, Kharasch E, Hoffer C, Risler L, Liu-Chen LY, Shen D (2006) Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites. Clin Pharmacol Ther 79:461–479

    Article  PubMed  CAS  Google Scholar 

  16. Andreassen TN, Klepstad P, Davies A, Bjordal K, Lundström S, Kaasa S, Dale O (2011) Influences on the pharmacokinetics of oxycodone: a multicentre cross-sectional study in 439 adult cancer patients. Eur J Clin Pharmacol. doi:10.1007/s00228-010-0948-5

  17. Kirvela M, Lindgren L, Seppala T, Olkkola K (1996) The pharmacokinetics of oxycodone in uremic patients undergoing renal transplantation. J Clin Anesth 8:13–18

    Article  PubMed  CAS  Google Scholar 

  18. Tallgren M, Olkkola KT, Seppala T, Hockerstedt K, Lindgren L (1997) Pharmacokinetics and ventilatory effects of oxycodone before and after liver transplantation. Clin Pharmacol Ther 61:655–661

    Article  PubMed  CAS  Google Scholar 

  19. Lugo RA, Kern SE (2004) The pharmacokinetics of oxycodone. J Pain Palliat Care Pharmacother 18(4):17–28

    Article  PubMed  Google Scholar 

  20. Edwards SR, Smith MT (2007) Low levels of oxycodone and its oxidative metabolites, noroxycodone, and oxymorphone, in rat plasma by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry. J Chromatogr 848:264–270

    Article  CAS  Google Scholar 

  21. Quigley C, Joel S, Patel N, Baksh A, Slevin M (2003) Plasma concentrations of morphine, morphine-6-glucuronide and morphine-3-glucuronide and their relationship with analgesia and side-effects in patients with cancer-related pain. Palliat Med 17:185–190

    Article  PubMed  Google Scholar 

  22. Cone E, Clarke J, Tsanaclis L (2007) Prevalence and disposition of drugs of abuse and opioid treatment drugs in oral fluid. J Anal Toxicol 31:424–433

    PubMed  CAS  Google Scholar 

  23. O'Neal C, Crouch D, Rollins D, Fatah AA (1999) Correlation of saliva codeine concentrations with plasma concentrations after oral codeine administration. J Anal Toxicol 23:452–459

    PubMed  Google Scholar 

  24. Pourzitaki C, Tachou H et al (2006) Heroin metabolites detection in saliva and blood. Rev Clin Pharmacol Pharmacokinet 20:108–109

    CAS  Google Scholar 

  25. Shiran M, Hassanzadeh-Khayyat M, Iqbal MZ et al (2005) Can saliva replace plasma for the monitoring of methadone? Ther Drug Monit 27:580–586

    Article  PubMed  CAS  Google Scholar 

  26. Kopecky E, Jacobsen S, Klein J, Bhushan K, Gideon K (1997) Correlation of morphine sulphate in blood plasma and saliva in pediatric patients. Ther Drug Monit 19:530–534

    Article  PubMed  CAS  Google Scholar 

  27. Skopp G, Pötsch L, Klinder K, Richter B, Aderjan R, Mattern R (2001) Saliva testing after single and chronic administration of dihydrocodeine. Int J Leg Med 114:133–140

    Article  CAS  Google Scholar 

  28. Okura T, Hattori A, Takano Y, Sato T et al (2008) Involvement of the pyrilamine transporter, a putative organic cation transporter, in blood-brain barrier transport of oxycodone. Drug Metab Dispos 36(10):2005–2013

    Article  PubMed  CAS  Google Scholar 

  29. Yabuuchi H, Tamai I, Nezu J, Sakamoto K et al (1999) Novel membrane transporter OCTN1 mediates multispecific, bidirectional, and pH-dependent transport of organic cation. J Pharmacol Exp Ther 289:768–773

    PubMed  CAS  Google Scholar 

  30. Genter MB, Krishan M, Augustine LM, Cherrington NJ (2010) Drug transporter expression and localization in rat nasal respiratory and olfactory mucosa and olfactory bulb. Drug Metab Dispos 38:1644–1647

    Article  PubMed  CAS  Google Scholar 

  31. Thompson SJ, Koszdin K, Bernards CM (2000) Opiate-induced analgesia is increased and prolonged in mice lacking P-glycoprotein. Anesthesiology 92:1392–1399

    Article  PubMed  CAS  Google Scholar 

  32. Boström E, Simonssen USH, Hammarlund-Udenaes M (2005) Oxycodone pharmacokinetics and pharmacodynamics in the rat in the presence of the P-glycoprotein inhibitor PSC833. J Pharm Sci 94:1060–1066

    Article  PubMed  Google Scholar 

  33. Hassan HE, Myers AL, Lee IJ, Coop A et al (2007) Oxycodone induces overexpression of P-glycoprotein (ABCB1) and affects paclitaxel's tissue distribution in Sprague Dawley rats. J Pharm Sci 96:2494–2506

    Article  PubMed  CAS  Google Scholar 

  34. Mercer SL, Coop A (2011). Opioid analgesics and P-glycoprotein efflux tranporters: a potential systems-level contribution to analgesic tolerance. Curr Top Med Chem (in press)

  35. Uematsu T, Yamaoka M, Matsuura T, Doto R et al (2001) P-glycoprotein expression in human major and minor salivary glands. Arch Oral Biol 46(6):521–527

    Article  PubMed  CAS  Google Scholar 

  36. Kandimalla KK, Donovan MD (2005) Localization and differential activity of P-glycoprotein in the bovine olfactory and nasal respiratory mucosa. Pharm Res 22(7):1121–1128

    Article  PubMed  CAS  Google Scholar 

  37. Yamahara H, Lee VHL (1993) Drug metabolism in the oral cavity. Adv Drug Deliv Rev 12:25–40

    Article  CAS  Google Scholar 

  38. Bosker W, Huestis M (2009) Oral fluid testing for drugs of abuse. Clin Chem 55(11):1910–1931

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This project was supported by grants from the Australian National Health and Medical Research Council and the Mater Health Services JP Kelly Research Fund.

Conflict of interest

None.

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Authors and Affiliations

  1. Department of Palliative and Supportive Care, Mater Health Services, Raymond Terrace, South Brisbane, QLD 4101, Australia

    Janet Hardy, Helen Anderson & Angela O’Shea

  2. Australian Centre for Paediatrics Pharmacokinetics, Mater Medical Research Institute, Brisbane, Australia

    Ross Norris

  3. School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Brisbane, Australia

    Bruce Charles

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  1. Janet Hardy
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  2. Ross Norris
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  3. Helen Anderson
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  4. Angela O’Shea
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  5. Bruce Charles
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Correspondence to Janet Hardy.

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Hardy, J., Norris, R., Anderson, H. et al. Is saliva a valid substitute for plasma in pharmacokinetic studies of oxycodone and its metabolites in patients with cancer?. Support Care Cancer 20, 767–772 (2012). https://doi.org/10.1007/s00520-011-1147-3

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  • DOI: https://doi.org/10.1007/s00520-011-1147-3

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