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British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 1991 Aug;32(2):167–172. doi: 10.1111/j.1365-2125.1991.tb03877.x

A method of studying pharmacokinetics in man at picomolar drug concentrations.

V J Cunningham 1, V W Pike 1, D Bailey 1, C A Freemantle 1, B C Page 1, A K Jones 1, M J Kensett 1, D Bateman 1, S K Luthra 1, T Jones 1
PMCID: PMC1368439  PMID: 1931467

Abstract

1. We describe a new method that enables the tissue kinetics of picomolar concentrations of drugs to be measured in man. The method is based on the administration of a drug, labelled with a short-lived positron-emitting radioisotope, such as carbon-11 (t1/2 = 20.4 min, beta + = 99.8%) or fluorine-18 (t1/2 = 109.8 min, beta + = 96.9%), which is then detected in vivo by an array of 10 large uncollimated sodium iodide scintillation detectors, arranged as five opposing pairs, with each pair collecting data over one major organ or region of the body. 2. To illustrate the scope of the new method we report the results of administering [O-methyl-11C]-diprenorphine, an established radioligand for central opiate (mu, kappa, and delta) receptors and L-6-[18F]-fluoro-DOPA, a marker for dopaminergic neurons. 3. Only 2-10 muCi (74-370 kBq) of radioactivity are used and, as a consequence of the high specific activities with which carbon-11 and fluorine-18 labelled compounds can be prepared, the method requires less than a nanomole of drug to be administered. In many cases, this amount of drug might be considered low enough to avoid any adverse biological effect. Furthermore repeat studies are possible in many without delivering unacceptable radiation burdens. 4. The high sensitivity realised for both radioactivity and mass suggests a mean for determining the human biodistribution of a new drug at a very early stage in its development. This has potential benefit to drug discovery programmes and to ensuing drug therapies.

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Selected References

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  1. Brodack J. W., Kilbourn M. R., Welch M. J., Katzenellenbogen J. A. NCA 16 alpha-[18F]fluoroestradiol-17 beta: the effect of reaction vessel on fluorine-18 resolubilization, product yield, and effective specific activity. Int J Rad Appl Instrum A. 1986;37(3):217–221. doi: 10.1016/0883-2889(86)90174-7. [DOI] [PubMed] [Google Scholar]
  2. Farde L., Hall H., Ehrin E., Sedvall G. Quantitative analysis of D2 dopamine receptor binding in the living human brain by PET. Science. 1986 Jan 17;231(4735):258–261. doi: 10.1126/science.2867601. [DOI] [PubMed] [Google Scholar]
  3. Frost J. J., Mayberg H. S., Sadzot B., Dannals R. F., Lever J. R., Ravert H. T., Wilson A. A., Wagner H. N., Jr, Links J. M. Comparison of [11C]diprenorphine and [11C]carfentanil binding to opiate receptors in humans by positron emission tomography. J Cereb Blood Flow Metab. 1990 Jul;10(4):484–492. doi: 10.1038/jcbfm.1990.90. [DOI] [PubMed] [Google Scholar]
  4. Garnett E. S., Firnau G., Nahmias C. Dopamine visualized in the basal ganglia of living man. Nature. 1983 Sep 8;305(5930):137–138. doi: 10.1038/305137a0. [DOI] [PubMed] [Google Scholar]
  5. HOWE C. T., EKINS R. P. THE BROMIDE SPACE AFTER THE INTRAVENOUS ADMINISTRATION OF 82BR. J Nucl Med. 1963 Nov;4:469–479. [PubMed] [Google Scholar]
  6. Jones A. K., Luthra S. K., Maziere B., Pike V. W., Loc'h C., Crouzel C., Syrota A., Jones T. Regional cerebral opioid receptor studies with [11C]diprenorphine in normal volunteers. J Neurosci Methods. 1988 Mar;23(2):121–129. doi: 10.1016/0165-0270(88)90184-7. [DOI] [PubMed] [Google Scholar]
  7. Lindvall O., Brundin P., Widner H., Rehncrona S., Gustavii B., Frackowiak R., Leenders K. L., Sawle G., Rothwell J. C., Marsden C. D. Grafts of fetal dopamine neurons survive and improve motor function in Parkinson's disease. Science. 1990 Feb 2;247(4942):574–577. doi: 10.1126/science.2105529. [DOI] [PubMed] [Google Scholar]
  8. Melega W. P., Hoffman J. M., Luxen A., Nissenson C. H., Phelps M. E., Barrio J. R. The effects of carbidopa on the metabolism of 6-[18F]fluoro-L-dopa in rats, monkeys and humans. Life Sci. 1990;47(2):149–157. doi: 10.1016/0024-3205(90)90228-j. [DOI] [PubMed] [Google Scholar]
  9. Nahmias C., Garnett E. S., Firnau G., Lang A. Striatal dopamine distribution in parkinsonian patients during life. J Neurol Sci. 1985 Jul;69(3):223–230. doi: 10.1016/0022-510x(85)90135-2. [DOI] [PubMed] [Google Scholar]
  10. Pike V. W., Kensett M. J., Turton D. R., Waters S. L., Silvester D. J. Labelled agents for PET studies of the dopaminergic system--some quality assurance methods, experience and issues. Int J Rad Appl Instrum A. 1990;41(5):483–492. doi: 10.1016/0883-2889(90)90009-6. [DOI] [PubMed] [Google Scholar]
  11. SUGURI S., OHTANI S., OSHINO M., YANAGISHITA K. The behavior of strontium-85 in a normal man following a single ingestion. Application of the whole body counter for the retention. Health Phys. 1963 May;9:529–535. doi: 10.1097/00004032-196305000-00008. [DOI] [PubMed] [Google Scholar]
  12. Skrabal F., Arnot R. N., Helus F., Glass H. I., Joplin G. F. A method for simultaneous electrolyte investigations in man using 77Br, 43K and 24Na. Int J Appl Radiat Isot. 1970 Apr;21(4):183–191. doi: 10.1016/0020-708x(70)90065-7. [DOI] [PubMed] [Google Scholar]
  13. Spinks T. J. Effect of size and composition of the body on absolute measurement of calcium in vivo. Phys Med Biol. 1979 Sep;24(5):976–987. doi: 10.1088/0031-9155/24/5/010. [DOI] [PubMed] [Google Scholar]

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