Skip to main content

Advertisement

SpringerLink
Log in

Blood–Brain Barrier Penetration of Zolmitriptan—Modelling of Positron Emission Tomography Data

  • Published:
Journal of Pharmacokinetics and Pharmacodynamics Aims and scope Submit manuscript

Abstract

Positron emissiontomography (PET) with the drug radiolabelled allows a direct measurement of brain or other organ kinetics, information which can be essential in drug development. Usually, however, a PET-tracer is administered intravenously (i.v.), whereas the therapeutic drug is mostly given orally or by a different route to the PET-tracer. In such cases, a recalculation is needed to make the PET data representative for the alternative administration route. To investigate the blood–brain barrier penetration of a drug (zolmitriptan) using dynamic PET and by PK modelling quantify the brain concentration of the drug after the nasal administration of a therapeutic dose. [11C]Zolmitriptan at tracer dose was administered as a short i.v. infusion and the brain tissue and venous blood kinetics of [11C]zolmitriptan was measured by PET in 7 healthy volunteers. One PET study was performed before and one 30 min after the administration of 5 mg zolmitriptan as nasal spray. At each of the instances, the brain radioactivity concentration after subtraction of the vascular component was determined up to 90 min after administration and compared to venous plasma radioactivity concentration after correction for radiolabelled metabolites. Convolution methods were used to describe the relationship between arterial and venous tracer concentrations, respectively between brain and arterial tracer concentration. Finally, the impulse response functions derived from the PET studies were applied on plasma PK data to estimate the brain zolmitriptan concentration after a nasal administration of a therapeutic dose. The studies shows that the PET data on brain kinetics could well be described as the convolution of venous tracer kinetics with an impulse response including terms for arterial-to-venous plasma and arterial-to-brain impulse responses. Application of the PET derived impulse responses on the plasma PK from nasal administration demonstrated that brain PK of zolmitriptan increased with time, achieving about 0.5 mg/ml at 30 min and close to a maximum of 1.5 mg/ml after 2 hr. A significant brain concentration was observed already after 5 min. The data support the notation of a rapid brain availability of zolmitriptan after nasal administration

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

Similar content being viewed by others

References

  1. Bergstrom M., Cass L.M., Valind S., Westerberg G., Lundberg E.L., Gray S., Bye A., Langstrom B. (1999). Deposition and disposition of [11C]zanamivir following administration as an intranasal spray. Evaluation with positron emission tomograph. Clin. Pharmacokinet. 36:33–39

    CAS  Google Scholar 

  2. Gefvert O., Bergstrom M., Langstrom B., Lundberg T., Lindstrom L., Yates R. (1998). Time course of central nervous dopamine-D2 and 5-HT2 receptor blockade and plasma drug concentrations after discontinuation of quetiapine (Seroquel) in patients with schizophrenia. Psychopharmacology (Berl) 135:119–126

    Article  CAS  Google Scholar 

  3. Gefvert O., Lundberg T., Wieselgren I.M., Bergstrom M., Langstrom B., Wiesel F., Lindstrom L. (2001). D(2) and 5HT(2A) receptor occupancy of different doses of quetiapine in schizophrenia: A PET study. Eur Neuropsychopharm. 11:105–110

    Article  CAS  Google Scholar 

  4. Hartvig P., Bergstrom M., Antoni G., Langstrom B. (2002). Positron emission tomography and brain monoamine neurotransmission–entries for study of drug interactions. Curr. Pharm. Des. 8:1417–1434

    Article  PubMed  CAS  Google Scholar 

  5. Kihlberg T., Karimi F., Langstrom B. (2002). [(11)C] Carbon monoxide in selenium-mediated synthesis of (11)C-carbamoyl compounds. J. Org. Chem. 67:3687–3692

    Article  PubMed  CAS  Google Scholar 

  6. Learned-Coughlin S.M., Bergstrom M., Savitcheva I., Ascher J., Schmith V.D., Langstrom B. (2003). In vivo activity of bupropion at the human dopamine transporter as measured by positron emission tomography. Biol. Psychiatry. 54:800–805

    Article  PubMed  CAS  Google Scholar 

  7. Lesko L.J., Rowland M., Peck C.C., Blaschke T.F. (2000). Optimizing the science of drug development: Opportunities for better candidate selection and accelerated evaluation in humans. Pharm. Res. 17:1335–1344

    Article  PubMed  CAS  Google Scholar 

  8. Peck C.C., Barr W.H., Benet L.Z., Collins J., Desjardins R.E., Furst D.E., Harter J.G., Levy G., Ludden T., Rodman J.H. et al. (1992). Opportunities for integration of pharmacokinetics, pharmacodynamics, and toxicokinetics in rational drug development. J. Pharm. Sci. 81:605–610

    Article  PubMed  CAS  Google Scholar 

  9. Lammertsma A.A. (2002). Radioligand studies: Imaging and quantitative analysis. Eur. Neuropsychopharm. 12:513–516

    Article  CAS  Google Scholar 

  10. Matarrese M., Salimbeni A., Turolla E.A., Turozzi D., Moresco R.M., Poma D., Magni F., Todde S., Rossetti C., Sciarrone M.T., Bianchi G., Kienle M.G., Fazio F. (2004). 11C-Radiosynthesis and preliminary human evaluation of the disposition of the ACE inhibitor [11C]zofenoprilat. Bioorg. Med. Chem. 12:603–611

    Article  PubMed  CAS  Google Scholar 

  11. Hutchinson O.C., Collingridge D.R., Barthel H., Price P.M., Aboagye E.O. (2003). Pharmacodynamics of radiolabelled anticancer drugs for positron emission tomography. Curr. Pharm. Des. 9:931–944

    Article  PubMed  CAS  Google Scholar 

  12. Propper D.J., de Bono J., Saleem A., Ellard S., Flanagan E., Paul J., Ganesan T.S., Talbot D.C., Aboagye E.O., Price P., Harris A.L., Twelves C. (2003). Use of positron emission tomography in pharmacokinetic studies to investigate therapeutic advantage in a phase I study of 120-hour intravenous infusion XR5000. J. Clin. Oncol. 21:203–210

    Article  PubMed  CAS  Google Scholar 

  13. Gulyas B., Halldin C., Sandell J., Karlsson P., Sovago J., Karpati E., Kiss B., Vas A., Cselenyi Z., Farde L. (2002). PET studies on the brain uptake and regional distribution of [11C] vinpocetine in human subjects. Acta. Neurol. Scand. 106:325–332

    Article  PubMed  CAS  Google Scholar 

  14. Bergstrom M., Grahnen A., Langstrom B. (2003). Positron emission tomography microdosing: A new concept with application in tracer and early clinical drug developmet. Eur. J. Clin. Pharmacol. 59:357–366

    Article  PubMed  Google Scholar 

  15. Bergstrom M., Nordberg A., Lunell E., Antoni G., Langstrom B. (1995). Regional deposition of inhaled 11C-nicotine vapor in the human airway as visualized by positron emission tomography. Clin. Pharmacol. Ther. 57:309–317

    Article  PubMed  CAS  Google Scholar 

  16. Uemura N., Charlesworth B.R., Onishi T., Mitaniyama A., Kaneko T., Ninomiya K., Nakamura K., Tateno M. (2003). Zomitriptan is detectable in plasma as early as 2 to 5 minutes after administration by nasal spray. Ann. Meeting Prog. Abstr. Headache: J. Head Face Pain 43:509–592, S159

    Google Scholar 

  17. M. Kågedahl, T. Duvauchelle, L. Hovesepian, B. R. Charlesworth, H.-L. Su, and R. A. Yates. Zolmitriptan demonstrates good pharmacokinetic consistency between and within individuals following intranasal administration. pA2 [serial online] 1: abstract 211P. Available from http://www.pa2online.org/ (2003).

  18. Gawel M., Aschoff J., May A., Charlesworth B.R. Zolmitriptan Nasal Spray: Efficacy, Onset of Action and Patient Satisfaction in Phases I and II of the REALIZE Study. Ann. Meeting Prog. Abstr. Headache: J. Head Face Pain 44:457–536, F23 (2004).

  19. Wall A., Kagedal M., Bergstrom M., Jacobsson E., Nilsson D., Antoni G., Frandberg P., Gustavsson S-A., Langstrom B., Yates R. (2005). Distribution of Zolmitriptan into the CNS in healthy volunteers. A positron emission tomography study. Drugs R D 6:139–147

    Article  PubMed  CAS  Google Scholar 

  20. Ebling W.F., Wada D.R., Stanski D.R. (1994). From piecewise to full physiologic pharmacokinetic modeling: Applied to thiopental disposition in the rat. J. Pharmacokinet. Biopharm. 22:259–292

    Article  PubMed  CAS  Google Scholar 

  21. Verotta D. (1989). An inequality-constrained least-squares deconvolution method. J. Pharmacokinet. Biopharm. 17:269–289

    Article  PubMed  CAS  Google Scholar 

  22. Pitsiu M., Gries J.M., Benowitz N., Gourlay S.G., Verotta D. (2002). Modeling nicotine arterial-venous differences to predict arterial concentrations and input based on venous measurements: Application to smokeless tobacco and nicotine gum. J. Pharmacokinet. Pharmacodyn. 29:383–402

    Article  PubMed  CAS  Google Scholar 

  23. Gunn R.N., Gunn S.R., Cunningham V.J. (2001). Positron emission tomography compartmental models. J. Cereb. Blood Flow Metab. 21:635–652

    Article  PubMed  CAS  Google Scholar 

  24. Gunn R.N., Gunn S.R., Turkheimer F.E., Aston J.A., Cunningham V.J. (2002). Positron emission tomography compartmental models: a basis pursuit strategy for kinetic modeling. J. Cereb. Blood Flow Metab. 22:1425–1439

    Article  PubMed  CAS  Google Scholar 

  25. Cunningham V.J., Jones T. (1993). Spectral analysis of dynamic PET studies. J. Cereb. Blood Flow Metab. 13:15–23

    CAS  Google Scholar 

  26. O’Hara T., Hayes S., Davis J., Devane J., Smart T., Dunne A. (2001). In vivo-in vitro correlation (IVIVC) modeling incorporating a convolution step. J. Pharmacokinet. Pharmacodyn. 28:277–298

    Article  PubMed  CAS  Google Scholar 

  27. Gomeni R., Dangeli C., Bye A. (2002). In silico prediction of optimal in vivo delivery properties using convolution-based model and clinical trial simulation. Pharm. Res. 19:99–103

    Article  PubMed  CAS  Google Scholar 

  28. Chiou W.L., Lam G., Chen M.L., Lee M.G. (1981). Arterial-venous plasma concentration differences of six drugs in the dog and rabbit after intravenous administration. Res. Commun. Chem. Pathol. Pharmacol. 32:27–39

    PubMed  CAS  Google Scholar 

  29. Porchet H.C., Benowitz N.L., Sheiner L.B., Copeland J.R. (1987). Apparent tolerance to the acute effect of nicotine results in part from distribution kinetics. J. Clin. Invest. 80:1466–1471

    Article  PubMed  CAS  Google Scholar 

  30. Tuk B., Herben V.M., Mandema J.W., Danhof M. (1998). Relevance of arteriovenous concentration differences in pharmacokinetic–pharmacodynamic modeling of midazolam. J. Pharmacol. Exp. Ther. 284:202–207

    PubMed  CAS  Google Scholar 

  31. Hirvonen J., Nagren K., Kajander J., Hietala J. (2001). Measurement of cortical dopamine d1 receptor binding with 11C[SCH23390]: A test-retest analysis. J. Cereb. Blood Flow Metab. 21:1133–1145

    PubMed  Google Scholar 

  32. Vilkman H., Kajander J., Nagren K., Oikonen V., Syvalahti E., Hietala J. (2000). Measurement of extrastriatal D2-like receptor binding with [11C]FLB 457–A test-retest analysis. Eur. J. Nucl. Med. 27:1666–1673

    Article  PubMed  CAS  Google Scholar 

  33. Hietala J., Nagren K., Lehikoinen P., Ruotsalainen U., Syvalahti E. (1999). Measurement of striatal D2 dopamine receptor density and affinity with [11C]-raclopride in vivo: A test-retest analysis. J. Cereb. Blood Flow Metab. 19:210–217

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Mats Bergström

    Present address: Novartis Pharma AG, WKL-135.1.73, CH-4002, Basel, Switzerland

  2. Roger Yates

    Present address: RayCandoc Ltd., Macclesfield, UK

Authors and Affiliations

  1. Uppsala Imanet AB, University Hospital, SE-751 85, Uppsala, Sweden

    Mats Bergström, Anders Wall, Stina Syvänen & Bengt Långström

  2. Department of Pharmaceutical Biosciences, Faculty of Pharmacy, Uppsala University, Uppsala, Sweden

    Mats Bergström & Stina Syvänen

  3. Alderly Parth, AstraZeneca, Macclesfield, UK

    Roger Yates

  4. AstraZeneca, Södertälje, UK

    Matts Kågedal

Authors
  1. Mats Bergström
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roger Yates
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anders Wall
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Matts Kågedal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stina Syvänen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bengt Långström
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mats Bergström.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bergström, M., Yates, R., Wall, A. et al. Blood–Brain Barrier Penetration of Zolmitriptan—Modelling of Positron Emission Tomography Data. J Pharmacokinet Pharmacodyn 33, 75–91 (2006). https://doi.org/10.1007/s10928-005-9001-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10928-005-9001-1

Keywords

Search

Navigation