Skip to main content
SpringerLink
Log in

Radiation Effects on Methamphetamine Pharmacokinetics and Pharmacodynamics in Rats

  • Original Research Article
  • Published:
European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objectives

Whole-body radiation exposure has been shown to alter the pharmacokinetics of certain drugs in both animal models and humans, but little is known about the effect of radiation on psychoactive medications. These drugs may have altered pharmacokinetics when administered during or after space travel or therapeutic or accidental radiation exposure, resulting in reduced efficacy or increased toxicity.

Methods

Methamphetamine was used to determine the effects of acutely administered 1, 3, and 6 Gy radiation on drug pharmacokinetics and pharmacodynamics. Male Wistar rats were exposed to 0, 1, 3, or 6 Gy X-ray radiation on day 0. The serum pharmacokinetics of subcutaneously administered 1 mg/kg methamphetamine was determined on day 3. Methamphetamine-induced (1 mg/kg) locomotor activity was measured on day 5. Brain methamphetamine concentrations were determined 2 h after methamphetamine administration (1 mg/kg) on day 6. Renal and hepatic serum biomarkers were assessed on days 3 and 6, with liver histology performed on day 6.

Results

While serum half-life and unchanged methamphetamine urine clearance were unaffected by any radiation dose, maximum methamphetamine concentrations and methamphetamine and amphetamine metabolite area under the serum concentration–time curve values from 0 to 300 min were significantly reduced after 6 Gy radiation exposure. Additionally, methamphetamine-induced locomotor activity and the brain to serum methamphetamine concentration ratio were significantly elevated after 6 Gy radiation.

Conclusions

While 1–6 Gy radiation exposure did not affect methamphetamine elimination, 6 Gy exposure had effects on both subcutaneous absorption and brain distribution. These effects should be considered when administering drugs during or after radiation exposure.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Hassler DM, Zeitlin C, Wimmer-Schweingruber RF, Ehresmann B, Rafkin S, Eigenbrode JL, et al. Mars’ surface radiation environment measured with the Mars Science Laboratory’s Curiosity rover. Science. 2014. https://doi.org/10.1126/science.1244797.

    Article  PubMed  Google Scholar 

  2. Zeitlin C, Hassler D, Cucinotta F, Ehresmann B, Wimmer-Schweingruber R, Brinza D, et al. Measurements of energetic particle radiation in transit to Mars on the Mars Science Laboratory. Science. 2013;340(6136):1080–4. https://doi.org/10.1126/science.1235989.

  3. Naderi F, Price H, Baker J. Humans to Mars: thoughts toward an executable program. In: Humans Orbiting Mars Workshop; 2015 Mar 31–Apr 1; Washington, DC.

  4. Steinert M, Weiss M, Gottlöber P, Belyi D, Gergel O, Bebeshko V, et al. Delayed effects of accidental cutaneous radiation exposure: fifteen years of follow-up after the Chernobyl accident. J Am Acad Dermatol. 2003;49(3):417–23. https://doi.org/10.1067/s0190-9622(03)02088-7.

    Article  PubMed  Google Scholar 

  5. Wong JY, Filippi AR, Dabaja BS, Yahalom J, Specht L. Total body irradiation: guidelines from the International Lymphoma Radiation Oncology Group (ILROG). Int J Radiat Oncol Biol Phys. 2018;101(3):521–9.

  6. Cenajek D, Chodera A, Wójciak Z, Szczawińska K, Kozaryn I. Cystamine effect on the pharmacokinetics of imipramine in radiation sickness. Acta Physiol Pol. 1980;31(2):123–9.

    CAS  PubMed  Google Scholar 

  7. Szczawińska K, Cenajek D, Chodera A, Wójciak Z. Pharmacodynamics and pharmacokinetics of psycholeptic drugs in the course of radiation disease. The effect of premedication with cystamine on pharmacodynamics and pharmacokinetics of nitrazepam. Acta Physiol Pol. 1977;28(2):161–8.

  8. Wojciak Z, Kozaryn I, Chodera A, Szczawinska K, Cenajek D. Changes of pharmacodynamics and pharmacokinetics of psycholeptic drugs in radiation sickness. Part 4. Changes in pharmacokinetics of thiroidazine. Nukleonika. 1977;22(4):355–60.

    CAS  Google Scholar 

  9. Moulder JE, Fish BL, Holcenberg JS, Sun G-X. Hepatic function and drug pharmacokinetics after total body irradiation plus bone marrow transplant. Int J Radiat Oncol Biol Phys. 1990;19(6):1389–96. https://doi.org/10.1016/0360-3016(90)90349-o.

    Article  CAS  PubMed  Google Scholar 

  10. Hsieh C-H, Hou M-L, Chiang M-H, Tai H-C, Tien H-J, Wang L-Y, et al. Head and neck irradiation modulates pharmacokinetics of 5-fluorouracil and cisplatin. J Transl Med. 2013;11(1):1–10. https://doi.org/10.1186/1479-5876-11-231.

    Article  Google Scholar 

  11. Tsai T-H, Chen Y-J, Hou M-L, Wang L-Y, Tai H-C, Hsieh C-H. Pelvic irradiation modulates the pharmacokinetics of cisplatin in the plasma and lymphatic system. Am J Transl Res. 2015;7(2):375.

    PubMed  PubMed Central  Google Scholar 

  12. Taylor C, Crosby I, Yip V, Maguire P, Pirmohamed M, Turner RM. A review of the important role of CYP2D6 in pharmacogenomics. Genes. 2020;11(11):1295. https://doi.org/10.3390/genes11111295.

    Article  CAS  PubMed Central  Google Scholar 

  13. Lin LY, Kumagai Y, Hiratsuka A, Narimatsu S, Suzuki T, Funae Y, et al. Cytochrome P4502D isozymes catalyze the 4-hydroxylation of methamphetamine enantiomers. Drug Metab Dispos. 1995;23(6):610–4.

    CAS  PubMed  Google Scholar 

  14. De La Torre R, Yubero-Lahoz S, Pardo-Lozano R, Farré M. MDMA, methamphetamine, and CYP2D6 pharmacogenetics: what is clinically relevant? Front Genet. 2012;3:235. https://doi.org/10.3389/fgene.2012.00235.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Milesi-Hallé A, Hendrickson HP, Laurenzana EM, Gentry WB, Owens SM. Sex-and dose-dependency in the pharmacokinetics and pharmacodynamics of (+)-methamphetamine and its metabolite (+)-amphetamine in rats. Toxicol Appl Pharmacol. 2005;209(3):203–13. https://doi.org/10.1016/j.taap.2005.04.007.

    Article  CAS  PubMed  Google Scholar 

  16. Cook CE, Jeffcoat AR, Hill JM, Pugh DE, Patetta PK, Sadler BM, et al. Pharmacokinetics of methamphetamine self-administered to human subjects by smoking S-(+)-methamphetamine hydrochloride. Drug Metab Dispos. 1993;21(4):717–23.

    CAS  PubMed  Google Scholar 

  17. Hambuchen MD, Berquist MD, Simecka CM, McGill MR, Gunnell MG, Hendrickson HP, et al. Effect of bile duct ligation-induced liver dysfunction on methamphetamine pharmacokinetics and locomotor activity in rats. J Pharm Pharm Sci. 2019;22:301–12. https://doi.org/10.18433/jpps30471.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gentry WB, Ghafoor AU, Wessinger WD, Laurenzana EM, Hendrickson HP, Owens SM. (+)-Methamphetamine-induced spontaneous behavior in rats depends on route of (+) methamphetamine administration. Pharmacol Biochem Behav. 2004;79(4):751–60. https://doi.org/10.1016/j.pbb.2004.10.006.

    Article  CAS  PubMed  Google Scholar 

  19. Berquist MD, McGill MR, Mazur A, Findley DL, Gorman G, Jones CB, et al. Effect of bile duct ligation-induced liver dysfunction on methamphetamine pharmacokinetics in male and female rats. Drug Alcohol Depend. 2020;215: 108190. https://doi.org/10.1016/j.drugalcdep.2020.108190.

    Article  CAS  PubMed  Google Scholar 

  20. Zhang Y, Huo M, Zhou J, Xie S. PKSolver: an add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel. Comput Methods Programs Biomed. 2010;99(3):306–14. https://doi.org/10.1016/j.cmpb.2010.01.007.

    Article  PubMed  Google Scholar 

  21. Lam F, Hung C, Perrier D. Estimation of variance for harmonic mean half-lives. J Pharm Sci. 1985;74(2):229–31. https://doi.org/10.1002/jps.2600740229.

    Article  CAS  PubMed  Google Scholar 

  22. Claassen V. Subcutaneous drug administration. In: Huston JP, editor. Neglected factors in pharmacology and neuroscience research: biopharmaceutics, animal characteristics, maintenance, testing conditions. Techniques in the behavioral and neural sciences, vol. 12. Amsterdam: Elsevier; 1994. pp. 35–45.

    Google Scholar 

  23. Reinhold H, Buisman G. Radiosensitivity of capillary endothelium. Br J Radiol. 1973;46(541):54–7. https://doi.org/10.1259/0007-1285-46-541-54.

    Article  CAS  PubMed  Google Scholar 

  24. Korpela E, Liu SK. Endothelial perturbations and therapeutic strategies in normal tissue radiation damage. Radiat Oncol. 2014;9(1):1–9. https://doi.org/10.1186/s13014-014-0266-7.

    Article  Google Scholar 

  25. Doll C, Durand R, Grulkey W, Sayer S, Olivotto I. Functional assessment of cutaneous microvasculature after radiation. Radiother Oncol. 1999;51(1):67–70. https://doi.org/10.1016/s0167-8140(99)00022-5.

    Article  CAS  PubMed  Google Scholar 

  26. Roth NM, Sontag MR, Kiani MF. Early effects of ionizing radiation on the microvascular networks in normal tissue. Radiat Res. 1999;151(3):270–7.

    Article  CAS  Google Scholar 

  27. Thanik VD, Chang CC, Zoumalan RA, Lerman OZ, Allen RJ Jr, Nguyen PD, et al. A novel mouse model of cutaneous radiation injury. Plast Reconstr Surg. 2011;127(2):560–8. https://doi.org/10.1097/prs.0b013e3181fed4f7.

    Article  CAS  PubMed  Google Scholar 

  28. Supersaxo A, Hein WR, Steffen H. Effect of molecular weight on the lymphatic absorption of water-soluble compounds following subcutaneous administration. Pharm Res. 1990;7(2):167–9. https://doi.org/10.1023/a:1015880819328.

    Article  CAS  PubMed  Google Scholar 

  29. Viola M, Sequeira J, Seiça R, Veiga F, Serra J, Santos AC, et al. Subcutaneous delivery of monoclonal antibodies: how do we get there? J Control Release. 2018;286:301–14. https://doi.org/10.1016/j.jconrel.2018.08.001.

    Article  CAS  PubMed  Google Scholar 

  30. Kim H, Park H, Lee SJ. Effective method for drug injection into subcutaneous tissue. Sci Rep. 2017;7(1):1–11. https://doi.org/10.1038/s41598-017-10110-w.

    Article  Google Scholar 

  31. Gradel AKJ, Porsgaard T, Lykkesfeldt J, Seested T, Gram-Nielsen S, Kristensen NR, et al. Factors affecting the absorption of subcutaneously administered insulin: effect on variability. J Diabetes Res. 2018. https://doi.org/10.1155/2018/1205121.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Brady ME, Hayton WL. GI drug absorption in rats exposed to cobalt-60 γ-radiation. II: In vivo rate of absorption. J Pharm Sci. 1977;66(3):366–70. https://doi.org/10.1002/jps.2600660315.

  33. Sokol GH, Greenblatt DJ, Lloyd BL, Georgotas A, Allen MD, Harmatz JS, et al. Effect of abdominal radiation therapy on drug absorption in humans. J Clin Pharmacol. 1978;18(8–9):388–96. https://doi.org/10.1002/j.1552-4604.1978.tb02454.x.

    Article  CAS  PubMed  Google Scholar 

  34. Hsieh C-H, Hsieh Y-J, Liu C-Y, Tai H-C, Huang Y-C, Shueng P-W, et al. Abdominal irradiation modulates 5-fluorouracil pharmacokinetics. J Transl Med. 2010;8(1):1–8. https://doi.org/10.1186/1479-5876-8-29.

    Article  CAS  Google Scholar 

  35. Liu J-H, Tsai T-H, Chen Y-J, Wang L-Y, Liu H-Y, Hsieh C-H. Local irradiation modulates the pharmacokinetics of metabolites in 5-fluorouracil—radiotherapy–pharmacokinetics phenomenon. Front Pharmacol. 2020. https://doi.org/10.3389/fphar.2020.00141.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Hsieh C-H, Hou M-L, Wang L-Y, Tai H-C, Tsai T-H, Chen Y-J. Local pelvic irradiation modulates pharmacokinetics of 5-fluorouracil in the plasma but not in the lymphatic system. BMC Cancer. 2015;15(1):1–7. https://doi.org/10.1186/s12885-015-1344-4.

    Article  CAS  Google Scholar 

  37. Hsieh C-H, Liu C-Y, Hsieh Y-J, Tai H-C, Wang L-Y, Tsai T-H, et al. Matrix metalloproteinase-8 mediates the unfavorable systemic impact of local irradiation on pharmacokinetics of anti-cancer drug 5-fluorouracil. PLoS ONE. 2011;6(6): e21000. https://doi.org/10.1371/journal.pone.0021000.

  38. Caldwell J, Dring L, Williams R. Biliary excretion of amphetamine and methamphetamine in the rat. Biochem J. 1972;129(1):25–9. https://doi.org/10.1042/bj1290025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lammers LA, Achterbergh R, de Vries EM, Van Nierop FS, Klümpen H-J, Soeters MR, et al. Short-term fasting alters cytochrome P450–mediated drug metabolism in humans. Drug Metab Dispos. 2015;43(6):819–28. https://doi.org/10.1124/dmd.114.062299.

    Article  CAS  PubMed  Google Scholar 

  40. Nakashima E, Yokogawa K, Ichimura F, Hashimoto T, Yamana T, Tsuji A. Effects of fasting on biperiden pharmacokinetics in the rat. J Pharm Sci. 1987;76(1):10–3. https://doi.org/10.1002/jps.2600760104.

    Article  CAS  PubMed  Google Scholar 

  41. Hvidberg E, Schou J. Subcutaneous absorption of urethane in dehydrated and fasted mice. Nature. 1959;184(4686):646–7. https://doi.org/10.1038/184646a0.

    Article  CAS  PubMed  Google Scholar 

  42. Itoh T, Murai S, Nagahama H, Miyate H, Abe E, Fujiwara H, et al. Effects of 24-h fasting on methamphetamine-and apomorphine-induced locomotor activities, and on monoamine metabolism in mouse corpus striatum and nucleus accumbens. Pharmacol Biochem Behav. 1990;35(2):391–6. https://doi.org/10.1016/0091-3057(90)90175-h.

    Article  CAS  PubMed  Google Scholar 

  43. Sándor N, Walter FR, Bocsik A, Sántha P, Schilling-Tóth B, Léner V, et al. Low dose cranial irradiation-induced cerebrovascular damage is reversible in mice. PLoS ONE. 2014;9(11):e112397. https://doi.org/10.1371/journal.pone.0112397.

  44. Mann H, Ladenheim B, Hirata H, Moran TH, Cadet JL. Differential toxic effects of methamphetamine (METH) and methylenedioxymethamphetamine (MDMA) in multidrug-resistant (mdr1a) knockout mice. Brain Res. 1997;769(2):340–6. https://doi.org/10.1016/s0006-8993(97)00754-3.

    Article  CAS  PubMed  Google Scholar 

  45. Bart J, Nagengast W, Coppes R, Wegman T, Van der Graaf W, Groen H, et al. Irradiation of rat brain reduces P-glycoprotein expression and function. Br J Cancer. 2007;97(3):322–6. https://doi.org/10.1038/sj.bjc.6603864.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Li X, Yang J, Qiao Y, Duan Y, Xin Y, Nian Y, et al. Effects of radiation on drug metabolism: a review. Curr Drug Metab. 2019;20(5):350–60. https://doi.org/10.2174/1389200220666190405171303.

    Article  CAS  PubMed  Google Scholar 

  47. Kitaichi K, Morishita Y, Doi Y, Ueyama J, Matsushima M, Zhao Y-L, et al. Increased plasma concentration and brain penetration of methamphetamine in behaviorally sensitized rats. Eur J Pharmacol. 2003;464(1):39–48. https://doi.org/10.1016/S0014-2999(03)01321-9.

    Article  CAS  PubMed  Google Scholar 

  48. Chiba S, Ro A, Ikawa T, Oide Y, Mukai T. Interactions of human organic anion transporters 1–4 and human organic cation transporters 1–3 with the stimulant drug methamphetamine and amphetamine. Leg Med. 2020;44: 101689. https://doi.org/10.1016/j.legalmed.2020.101689.

    Article  CAS  Google Scholar 

  49. Jongejan H, Der Kogel AB, Provoost A, Molenaar J. Radiation nephropathy in young and adult rats. Int J Radiat Oncol Biol Phys. 1987;13(2):225–32. https://doi.org/10.1016/0360-3016(87)90131-3.

    Article  CAS  PubMed  Google Scholar 

  50. Hosten AO. BUN and creatinine. In: Walker HK, Hall WD, Hurst JW, editors. Clinical methods: the history, physical, and laboratory examinations. 3rd ed. Boston: Butterworths; 1990.

    Google Scholar 

  51. Chung K, Bang S, Kim Y, Chang H. Intraoperative severe hypoglycemia indicative of post-hepatectomy liver failure. J Anesth. 2016;30(1):148–51. https://doi.org/10.1007/s00540-015-2070-4.

    Article  PubMed  Google Scholar 

  52. Anno T, Kaneto H, Shigemoto R, Kawasaki F, Kawai Y, Urata N, et al. Hypoinsulinemic hypoglycemia triggered by liver injury in elderly subjects with low body weight. Endocrinol Diabetes Metab Case Rep. 2018. https://doi.org/10.1530/edm-17-0155.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Abdelhalim MAK, Moussa SAA. The biochemical changes in rats blood serum levels exposed to different gamma radiation doses. Afr J Pharm Pharmacol. 2013;7(15):785–92. https://doi.org/10.5897/AJPP2013.3434.

    Article  CAS  Google Scholar 

  54. Imaeda M, Ishikawa H, Yoshida Y, Takahashi T, Ohkubo Y, Musha A, et al. Long-term pathological and immunohistochemical features in the liver after intraoperative whole-liver irradiation in rats. J Radiat Res. 2014;55(4):665–73. https://doi.org/10.1093/jrr/rru005.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Cheng W, Xiao L, Ainiwaer A, Wang Y, Wu G, Mao R, et al. Molecular responses of radiation-induced liver damage in rats. Mol Med Rep. 2015;11(4):2592–600. https://doi.org/10.3892/mmr.2014.3051.

    Article  CAS  PubMed  Google Scholar 

  56. Gaber MW, Rodgers SP, Tang TT, Sabek OM, Zawaski JA. Differentiation of heterogeneous radiation exposure using hematology and blood chemistry. Radiat Res. 2020;193(1):24–33. https://doi.org/10.1667/rr15411.1.

    Article  CAS  PubMed  Google Scholar 

  57. Sukumaran M, Bloom WL. Influence of diet on serum alkaline phosphatase in rats and men. Proc Soc Exp Biol Med. 1953;84(3):631–4. https://doi.org/10.3181/00379727-84-20735.

    Article  CAS  PubMed  Google Scholar 

  58. Waner T, Nyska A. The influence of fasting on blood glucose, triglycerides, cholesterol, and alkaline phosphatase in rats. Vet Clin Pathol. 1994;23(3):78–80. https://doi.org/10.1111/j.1939-165x.1994.tb00683.x.

    Article  PubMed  Google Scholar 

  59. Gasteyger C, Larsen TM, Vercruysse F, Astrup A. Effect of a dietary-induced weight loss on liver enzymes in obese subjects. Am J Clin Nutr. 2008;87(5):1141–7. https://doi.org/10.1093/ajcn/87.5.1141.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Environmental and Occupational Health, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR, 72205, USA

    Mitchell R. McGill

  2. Department of Pharmaceutical Science, Marshall University School of Pharmacy, Kopp Hall 353, 1 John Marshall Drive, Huntington, WV, 25755, USA

    David L. Findley, Eric R. Blough & Michael D. Hambuchen

  3. Department of Biomedical Science, Marshall University School of Medicine, 1 John Marshall Drive, Huntington, WV, 25755, USA

    Anna Mazur

  4. Department of Pathology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA

    Eric U. Yee & Felicia D. Allard

  5. Office of Radiation Safety, Marshall University, 1 John Marshall Drive, Huntington, WV, 25755, USA

    Allison Powers

  6. Department of Pharmaceutical, Social and Administrative Sciences, Samford University McWhorter School of Pharmacy, 800 Lakeshore Drive, Birmingham, AL, 35229, USA

    Lori Coward & Greg Gorman

Authors
  1. Mitchell R. McGill
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David L. Findley
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anna Mazur
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eric U. Yee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Felicia D. Allard
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Allison Powers
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lori Coward
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Eric R. Blough
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Greg Gorman
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Michael D. Hambuchen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael D. Hambuchen.

Ethics declarations

Funding

This work was supported by the NASA WV EPSCoR Research Seed Grant.

Conflicts of interest

The authors have no conflicts of interest to disclose.

Ethics approval

Rat use for these experiments was approved by the Marshall University Institutional Animal Care and Use Committee (Protocol #717), and was conducted in accordance with the Guide for the Care and Use of Laboratory Animals as adopted by the National Institutes of Health.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and material

The data in the current study are available from the corresponding author on reasonable request.

Code availability

Not applicable.

Author contributions

Data collection (MRM, DLF, AM, AP, LC, GG, MDH), data analysis (MRM, EUY, FDA, ERB, GG, MDH), funding (ERB, MDH), experimental design (MRM, ERB, GG, MDH).

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 204 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

McGill, M.R., Findley, D.L., Mazur, A. et al. Radiation Effects on Methamphetamine Pharmacokinetics and Pharmacodynamics in Rats. Eur J Drug Metab Pharmacokinet 47, 319–330 (2022). https://doi.org/10.1007/s13318-022-00755-y

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13318-022-00755-y

Search

Navigation