Abstract
Quantification of target site pharmacokinetics (PK) is crucial for drug discovery and development. Clinical micro-dialysis (MD) has increasingly been employed for the description of drug distribution and receptor phase PK of the unbound fraction of various analytes. Costs for MD experiments are comparably low and given suitable analytics, target tissue PK of virtually any drug molecule can be quantified. The major limitation of MD stems from the fact that organs such as brain, lung or liver are not readily accessible without surgery. Recently, non-invasive imaging techniques, i.e. positron emission tomography (PET) or magnetic resonance spectroscopy (MRS), have become available for in vivo drug distribution assessment and allow for drug concentration measurements in practically every human organ. Spatial resolution of MRS imaging, however, is low and although PET enables monitoring of regional drug concentration differences with a spatial resolution of a few millimetres, discrimination between bound and unbound drug or parent compound and metabolite is difficult. Radiotracer development is furthermore time and labour intensive and requires special expertise and radiation exposure and costs originating from running a PET facility cannot be neglected. The recent complementary use of MD and imaging has permitted to exploit individual strengths of these diverse techniques. In conclusion, MD and imaging techniques have provided drug distribution data that have so far not been available. Used alone or in combination, these methods may potentially play an important role in future drug research and development with the potential to serve as translational tools for clinical decision making.
Keywords: microdialysis, drug distribution, positron emission tomography (PET), magnetic resonance spectroscopy (MRS), in vivo
Full Text
The Full Text of this article is available as a PDF (190.4 KB).
References
- 1.Evans WE, Relling MV. Moving towards individualized medicine with pharmacogenomics. Nature. 2004;429:464–468. doi: 10.1038/nature02626. [DOI] [PubMed] [Google Scholar]
- 2.Rowland M, Tozer TN. Concentration Monitoring. In: Balado D, Klass F, Stead L, Forsyth L, Magee RD, editors. Clinical Pharmacokinetics: Concepts and Applications. 3rd ed. Baltimore, MD: Lippincott, Williams & Wilkins; 1995. pp. 290–309. [Google Scholar]
- 3.Müller M, dela Pena A, Derendorf H. Issues in pharmacokinetics and pharmacodynamics of anti-infective agents: distribution in tissue. Antimicrob Agents Chemother. 2004;48:1441–1453. doi: 10.1128/AAC.48.5.1441-1453.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Müller M, Mader RM, Steiner B, et al. 5-Fluorouracil kinetics in the interstitial tumor space: clinical response in breast cancer patients. Cancer Res. 1997;57:2598–2601. [PubMed] [Google Scholar]
- 5.Presant CA, Wolf W, Waluch V, et al. Association of intratumoral pharmacokinetics of fluorouracil with clinical respouse. Lancet. 1994;343:1184–1187. doi: 10.1016/S0140-6736(94)92399-X. [DOI] [PubMed] [Google Scholar]
- 6.Eichler HG, Müller M. Drug distribution: the forgotten relative in clinical pharmacokinetics. Clin Pharmacokinet. 1998;34:95–109. doi: 10.2165/00003088-199834020-00001. [DOI] [PubMed] [Google Scholar]
- 7.Elmquist WF, Sawchuk RJ. Application of microdialysis in pharmacokinetic studies. Pharm Res. 1997;14:267–288. doi: 10.1023/A:1012081501464. [DOI] [PubMed] [Google Scholar]
- 8.Müller M. Microdialysis in clinical drug delivery studies. Adv Drug Deliv Rev. 2000;45:255–269. doi: 10.1016/S0169-409X(00)00113-7. [DOI] [PubMed] [Google Scholar]
- 9.Joukhadar C, Müller M. Microdialysis: current applications in clinical pharmacokinetic studies and its potential role in the future. Clin Pharmacokinet. 2005;44:895–913. doi: 10.2165/00003088-200544090-00002. [DOI] [PubMed] [Google Scholar]
- 10.Jynge P, Skjetne T, Gribbestad I, et al. In vivo tissue pharmacokinetics by fluorine magnetic resonance spectroscopy: a study of liver and muscle disposition of fleroxacin in humans. Clin Pharmacol Ther. 1990;48:481–489. doi: 10.1038/clpt.1990.183. [DOI] [PubMed] [Google Scholar]
- 11.Port RE, Wolf W. Noninvasive methods to study drug distribution. Invest New Drugs. 2003;21:157–168. doi: 10.1023/A:1023569328717. [DOI] [PubMed] [Google Scholar]
- 12.Langer O, Müller M. Methods to assess tissue-specific distribution and metabolism of drugs. Curr Drug Metab. 2004;5:463–481. doi: 10.2174/1389200043335379. [DOI] [PubMed] [Google Scholar]
- 13.Fischman AJ, Livni E, Babich J, et al. Pharmacokinetics of [18F]fleroxacin in healthy human subjects studies by using positron emission tomography. Antimicrob Agents Chemother. 1993;37:2144–2152. doi: 10.1128/aac.37.10.2144. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Fischman AJ, Alpert NM, Rubin RH. Pharmacokinetic imaging: a noninvasive method for determining drug distribution and action. Clin Pharmacokinet. 2002;41:581–602. doi: 10.2165/00003088-200241080-00003. [DOI] [PubMed] [Google Scholar]
- 15.FDA/Center for Drug Evaluation and Research. Food and Drug Administration Web site. Available at: http://www.fda.gov/cder/present/anti-infective798/073198.pdf. Accessed October 4, 2005.
- 16.FDA/Center for Drug Evaluation and Research. Food and Drug Administration Web site. Available at: http://www.fda.gov/cder/guidance/2580dft.pdf. Accessed October 4, 2005.
- 17.Stahle L, Arner P, Ungerstedt U. Drug distribution studies with microdialysis. III. Extracellular concentration of caffeine in adipose tissue in man. Life Sci. 1991;49:1853–1858. doi: 10.1016/0024-3205(91)90488-W. [DOI] [PubMed] [Google Scholar]
- 18.Ungerstedt U, Rostami E. Microdialysis in neurointensive care. Curr Pharm Des. 2004;10:2145–2152. doi: 10.2174/1381612043384105. [DOI] [PubMed] [Google Scholar]
- 19.Pickup JC, Hussain F, Evans ND, Sachedina N. In vivo glucose monitoring: the clinical reality and the promise. Biosens Bioelectron. 2005;20:1897–1902. doi: 10.1016/j.bios.2004.08.016. [DOI] [PubMed] [Google Scholar]
- 20.de la Pena A, Liu P, Derendorf H. Microdialysis in peripheral tissues. Adv Drug Deliv Rev. 2000;45:189–216. doi: 10.1016/S0169-409X(00)00106-X. [DOI] [PubMed] [Google Scholar]
- 21.Hamrin K, Henriksson J. Local effect of vanadate on interstitial glucose and lactate concentrations in human skeletal muscle. Life Sci. 2005;76:2329–2338. doi: 10.1016/j.lfs.2004.11.008. [DOI] [PubMed] [Google Scholar]
- 22.Ekstrom PO, Andersen A, Saeter G, Giercksky KE, Slordal L. Continuous intratumoral microdialysis during high-dose methotrexate therapy in a patient with malignant fibrous histiocytoma of the femur: a case report. Cancer Chemother Pharmacol. 1997;39:267–272. doi: 10.1007/s002800050571. [DOI] [PubMed] [Google Scholar]
- 23.Joukhadar C, Derendorf H, Müller M. Microdialysis: a novel tool for clinical studies of anti-infective agents. Eur J Clin Pharmacol. 2001;57:211–219. doi: 10.1007/s002280100301. [DOI] [PubMed] [Google Scholar]
- 24.Brunner M, Müller M. Microdialysis: an in vivo approach for measuring drug delivery in oncology. Eur J Clin Pharmacol. 2002;58:227–234. doi: 10.1007/s00228-002-0475-0. [DOI] [PubMed] [Google Scholar]
- 25.Delacher S, Derendorf H, Hollenstein U, et al. A combined in vivo pharmacokinetic-in vitro pharmacodynamic approach to simulate target site pharmacodynamics of antibiotics in humans. J Antimicrob Chemother. 2000;46:733–739. doi: 10.1093/jac/46.5.733. [DOI] [PubMed] [Google Scholar]
- 26.Bur A, Joukhadar C, Klein N, et al. Effect of exercise on transdermal nicotine release in healthy habitual smokers. Int J Clin Pharmacol Ther. 2005;43:239–243. doi: 10.5414/cpp43239. [DOI] [PubMed] [Google Scholar]
- 27.Alfredson H, Lorentzon R. Intratendinous glutamate levels and eccentric training in chronic Achilles tendinosis: a prospective study using microdialysis technique. Knee Surg Sports Traumatol Arthrosc. 2003;11:196–199. doi: 10.1007/s00167-003-0391-6. [DOI] [PubMed] [Google Scholar]
- 28.Tegeder I, Brautigam L, Seegel M, et al. Cisplatin tumor concentrations after intra-arterial cisplatin infusion or embolization in patients with oral cancer. Clin Pharmacol Ther. 2003;73:417–426. doi: 10.1016/S0009-9236(03)00008-0. [DOI] [PubMed] [Google Scholar]
- 29.Mader RM, Schrolnberger C, Rizovski B, et al. Penetration of capecitabine and its metabolites into malignant and healthy tissues of patients with advanced breast cancer. Br J Cancer. 2003;88:782–787. doi: 10.1038/sj.bjc.6600809. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Bergenheim AT, Capala J, Roslin M, Henriksson R. Distribution of BPA and metabolic assessment in glioblastoma patients during BNCT treatment: a microdialysis study. J Neurooncol. 2005;71:287–293. doi: 10.1007/s11060-004-1724-0. [DOI] [PubMed] [Google Scholar]
- 31.Chang YL, Tsai PL, Chou YC, Tien JH, Tsai TH. Simultaneous determinatin of nicotine and its metabolite, cotinine, in rat blood and brain tissue using microdialysis coupled with liquid chromatography: pharmacokinetic application. J Chromatogr A. 2005;1088:152–157. doi: 10.1016/j.chroma.2005.01.042. [DOI] [PubMed] [Google Scholar]
- 32.Engstrom M, Polito A, Reinstrup P, et al. Intracerebral microdialysis in severe brain trauma: the importance of catheter location. J Neurosurg. 2005;102:460–469. doi: 10.3171/jns.2005.102.3.0460. [DOI] [PubMed] [Google Scholar]
- 33.Ederoth P, Tunblad K, Bouw R, et al. Blood-brain barrier transport of morphine in patients with severe brain trauma. Br J Clin Pharmacol. 2004;57:427–435. doi: 10.1046/j.1365-2125.2003.02032.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Herkner H, Muller MR, Kreischitz N, et al. Closed-chest microdialysis to measure antibiotic penetration into human lung tissue. Am J Respir Crit Care Med. 2002;165:273–276. doi: 10.1164/ajrccm.165.2.2106082. [DOI] [PubMed] [Google Scholar]
- 35.Tomaselli F, Maier A, Matzi V, Smolle-Juttner FM, Dittrich P. Penetration of meropenem into pneumonic human lung tissue as measured by in vivo microdialysis. Antimicrob Agents Chemother. 2004;48:2228–2232. doi: 10.1128/AAC.48.6.2228-2232.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Thorsen K, Kristoffersson AO, Lerner UH, Lorentzon RP. In situ microdialysis in bone tissue: stimulation of prostaglandin E2 release by weight-bearing mechanical loading. J Clin Invest. 1996;98:2446–2449. doi: 10.1172/JCI119061. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Bahlmann L, Misfeld M, Klaus S, et al. Myocardial redox state during coronary artery bypass grafting assessed with microdialysis. Intensive Care Med. 2004;30:889–894. doi: 10.1007/s00134-004-2199-3. [DOI] [PubMed] [Google Scholar]
- 38.Nowak G, Ungerstedt J, Wernerman J, Ungerstedt U, Ericzon BG. Clinical experience in continuous graft monitoring with microdialysis early after liver transplantation. Br J Surg. 2002;89:1169–1175. doi: 10.1046/j.1365-2168.2002.02187.x. [DOI] [PubMed] [Google Scholar]
- 39.Jansson K, Jansson M, Andersson M, Magnuson A, Ungerstedt U, Norgren L. Normal values and differences between intraperitoneal and subcutaneous microdialysis in patients after non-complicated gastrointestinal surgery. Scand J Clin Lab Invest. 2005;65:273–281. doi: 10.1080/00365510510013802. [DOI] [PubMed] [Google Scholar]
- 40.Plock N, Kloft C. Microdialysis: theoretical background and recent implementation in applied life-sciences. Eur J Pharm Sci. 2005;25:1–24. doi: 10.1016/j.ejps.2005.01.017. [DOI] [PubMed] [Google Scholar]
- 41.Kreilgaard M. Assessment of cutaneous drug delivery using microdialysis. Adv Drug Deliv Rev. 2002;54:S99–S121. doi: 10.1016/S0169-409X(02)00117-5. [DOI] [PubMed] [Google Scholar]
- 42.Müller M. Science, medicine, and the future: microdialysis. BMJ. 2002;324:588–591. doi: 10.1136/bmj.324.7337.588. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Müller M, Haag O, Burgdorff T, et al. Characterization of peripheral-compartment kinetics of antibiotics by in vivo microdialysis in humans. Antimicrob Agents Chemother. 1996;40:2703–2709. doi: 10.1128/aac.40.12.2703. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Benfeldt E, Serup J, Menne T. Microdialysis vs suction blister technique for in vivo sampling of pharmacokinetics in the human dermis. Acta Derm Venereol. 1999;79:338–342. doi: 10.1080/000155599750010210. [DOI] [PubMed] [Google Scholar]
- 45.Day RM, Harbord M, Forbes A, Segal AW. Cantharidin blisters: a technique for investigating leukocyte trafficking and cytokine production at sites of inflammation in humans. J Immunol Methods. 2001;257:213–220. doi: 10.1016/S0022-1759(01)00467-7. [DOI] [PubMed] [Google Scholar]
- 46.Ryan DM. Pharmacokinetics of antibiotics in natural and experimental superficial compartments in animals and humans. J Antimicrob Chemother. 1993;31:1–16. doi: 10.1093/jac/31.1.1. [DOI] [PubMed] [Google Scholar]
- 47.Brunner M, Stabeta H, Moller JG, et al. Target site concentrations of ciprofloxacin after single intravenous and oral doses. Antimicrob Agents Chemother. 2002;46:3724–3730. doi: 10.1128/AAC.46.12.3724-3730.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48.Müller M, Stass H, Brunner M, Moller JG, Lackner E, Eichler HG. Penetration of moxifloxacin into peripheral compartments in humans. Antimicrob Agents Chemother. 1999;43:2345–2349. doi: 10.1128/aac.43.10.2345. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.Brunner M, Schmiedberger A, Schmid R, et al. Direct assessment of peripheral pharmacokinetics in humans: comparison between cantharides blister fluid sampling, in vivo microdialysis and saliva sampling. Br J Clin Pharmacol. 1998;46:425–431. doi: 10.1046/j.1365-2125.1998.00805.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50.Müller M, Brunner M, Schmid R, et al. Comparison of three different experimental methods for the assessment of peripheral compartment pharmacokinetics in humans. Life Sci. 1998;62:PL227–PL234. doi: 10.1016/S0024-3205(98)00071-X. [DOI] [PubMed] [Google Scholar]
- 51.Wolf W, Presant CA, Waluch V. 19F-MRS studies of fluorinated drugs in humans. Adv Drug Deliv Rev. 2000;41:55–74. doi: 10.1016/S0169-409X(99)00056-3. [DOI] [PubMed] [Google Scholar]
- 52.Fischman AJ, Alpert NM, Babich JW. The role of positron emission tomography in pharmacokinetic analysis. Drug Metab Rev. 1997;29:923–956. doi: 10.3109/03602539709002238. [DOI] [PubMed] [Google Scholar]
- 53.Pien HH, Fischman AJ, Thrall JH, Sorensen AG. Using imaging biomarkers to accelerate drug development and clinical trials. Drug Discov Today. 2005;10:259–266. doi: 10.1016/S1359-6446(04)03334-3. [DOI] [PubMed] [Google Scholar]
- 54.Phelps ME. PET: the merging of biology and imaging into molecular imaging. J Nucl Med. 2000;41:661–681. [PubMed] [Google Scholar]
- 55.Fischman AJ, Babich JW, Bonab AA, et al. Pharmacokinetics of [18F]trovafloxacin in healthy human subjects studied with positron emission tomography. Antimicrob Agents Chemother. 1998;42:2048–2054. doi: 10.1128/aac.42.8.2048. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56.Brunner M, Langer O, Dobrozemsky G, et al. [18F]Ciprofloxacin, a new positron emission tomography tracer for noninvasive assessment of the tissue distribution and pharmacokinetics of ciprofloxacin in humans. Antimicrob Agents Chemother. 2004;48:3850–3857. doi: 10.1128/AAC.48.10.3850-3857.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57.Singh M, Waluch V. Physics and instrumentation for imaging in-vivo drug distribution. Adv Drug Deliv Rev. 2000;41:7–20. doi: 10.1016/S0169-409X(99)00053-8. [DOI] [PubMed] [Google Scholar]
- 58.Lyoo IK, Renshaw PF. Magnetic resonance spectroscopy: current and future applications in psychiatric research. Biol Psychiatry. 2002;51:195–207. doi: 10.1016/S0006-3223(01)01313-0. [DOI] [PubMed] [Google Scholar]
- 59.Griffiths JR, Glickson JD. Monitoring pharmacokinetics of anticancer drugs: non-invasive investigation using magnetic resonance spectroscopy. Adv Drug Deliv Rev. 2000;41:75–89. doi: 10.1016/S0169-409X(99)00057-5. [DOI] [PubMed] [Google Scholar]
- 60.Fischman AJ, Livni E, Babich JW, et al. Pharmacokinetics of [18F]fleroxacin in patients with acute exacerbations of chronic bronchitis and complicated urinary tract infection studied by positron emission tomography. Antimicrob Agents Chemother. 1996;40:659–664. doi: 10.1128/aac.40.3.659. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61.Fischman AJ, Alpert NM, Livni E, et al. Pharmacokinetics of 18F-labeled fluconazole in healthy human subjects by positron emission tomography. Antimicrob Agents Chemother. 1993;37:1270–1277. doi: 10.1128/aac.37.6.1270. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62.Berridge MS, Lee Z, Heald DL. Regional distribution and kinetics of inhaled pharmaceuticals. Curr Pharm Des. 2000;6:1631–1651. doi: 10.2174/1381612003398852. [DOI] [PubMed] [Google Scholar]
- 63.Langer O, Brunner M, Zeitlinger M, et al. In vitro and in vivo evaluation of [18F]ciprofloxacin for the imaging of bacterial infections with PET. Eur J Nucl Med Mol Imaging. 2005;32:143–150. doi: 10.1007/s00259-004-1646-2. [DOI] [PubMed] [Google Scholar]
- 64.Brunner M, Langer O, Sunder-Plassmann R, et al. Influence of functional haplotypes in the drug transporter gene ABCB1 on central nervous sytem drug distribution in humans. Clin Pharmacol Ther. 2005;78:182–190. doi: 10.1016/j.clpt.2005.04.011. [DOI] [PubMed] [Google Scholar]
- 65.Gupta N, Price PM, Aboagye EO. PET for in vivo pharmacokinetic and pharmacodynamic measurements. Eur J Cancer. 2002;38:2094–2107. doi: 10.1016/S0959-8049(02)00413-6. [DOI] [PubMed] [Google Scholar]
- 66.Moehler M, Dimitrakopoulou-Strauss A, Gutzler F, Raeth U, Strauss LG, Stremmel W. 18F-labeled fluorouracil positron emission tomography and the prognoses of colorectal carcinoma patients with metastases to the liver treated with 5-fluorouracil. Cancer. 1998;83:245–253. doi: 10.1002/(SICI)1097-0142(19980715)83:2<245::AID-CNCR7>3.0.CO;2-P. [DOI] [PubMed] [Google Scholar]
- 67.Saleem A, Brown GD, Brady F, et al. Metabolic activation of temozolomide measured in vivo using positron emission tomography. Cancer Res. 2003;63:2409–2415. [PubMed] [Google Scholar]
- 68.Noske DP, Peerdeman SM, Comans EF, et al. Cerebral microdialysis and positron emission tomography after surgery for aneurysmal subarachnoid hemorrhage in grade I patients. Surg Neurol. 2005;64:109–115. doi: 10.1016/j.surneu.2004.09.036. [DOI] [PubMed] [Google Scholar]
- 69.Hutchinson PJ, Gupta AK, Fryer TF, et al. Correlation between cerebral blood flow, substrate delivery, and metabolism in head injury: a combined microdialysis and triple oxygen positron emission tomography study. J Cereb Blood Flow Metab. 2002;22:735–745. doi: 10.1097/00004647-200206000-00012. [DOI] [PubMed] [Google Scholar]
- 70.Hillered L, Vespa PM, Hovda DA. Translational neurochemical research in acute human brain injury: the current status and potential future for cerebral microdialysis. J Neurotrauma. 2005;22:3–41. doi: 10.1089/neu.2005.22.3. [DOI] [PubMed] [Google Scholar]
- 71.Clausen T, Alves OL, Reinert M, Doppenberg E, Zauner A, Bullock R. Association between elevated brain tissue glycerol levels and poor outcome following severe traumatic brain injury. J Neurosurg. 2005;103:233–238. doi: 10.3171/jns.2005.103.2.0233. [DOI] [PubMed] [Google Scholar]
- 72.Cavus I, Kasoff WS, Cassaday MP, et al. Extracellular metabolites in the cortex and hippocampus of epileptic patients. Ann Neurol. 2005;57:226–235. doi: 10.1002/ana.20380. [DOI] [PubMed] [Google Scholar]
- 73.Vespa P, Bergsneider M, Hattori N, et al. Metabolic crisis without brain ischemia is common after traumatic brain injury: a combined microdialysis and positron emission tomography study. J Cereb Blood Flow Metab. 2005;25:763–774. doi: 10.1038/sj.jcbfm.9600073. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 74.Bosche B, Dohmen C, Graf R, et al. Extracellular concentrations of non-transmitter amino acids in peri-infarct tissue of patients predict malignant middle cerebral artery infarction. Stroke. 2003;34:2908–2913. doi: 10.1161/01.STR.0000100158.51986.EB. [DOI] [PubMed] [Google Scholar]
- 75.Enblad P, Valtysson J, Andersson J, et al. Simultaneous intracerebral microdialysis and positron emission tomography in the detection of ischemia in patients with subarachnoid hemorrhage. J Cereb Blood Flow Metab. 1996;16:637–644. doi: 10.1097/00004647-199607000-00014. [DOI] [PubMed] [Google Scholar]
- 76.Hutchinson PJ, Gupta AK, Fryer TF, et al. Correlation between cerebral blood flow, substrate delivery, and metabolism in head injury: a combined microdialysis and triple oxygen positron emission tomography study. J Cereb Blood Flow Metab. 2002;22:735–745. doi: 10.1097/00004647-200206000-00012. [DOI] [PubMed] [Google Scholar]
- 77.Dohmen C, Bosche B, Graf R, et al. Prediction of malignant course in MCA infarction by PET and microdialysis. Stroke. 2003;34:2152–2158. doi: 10.1161/01.STR.0000083624.74929.32. [DOI] [PubMed] [Google Scholar]
- 78.Virtanen KA, Peltoniemi P, Marjamaki P, et al. Human adipose tissue glucose uptake determined using [(18)F]-fluoro-deoxy-glucose ([(18)F]FDG) and PET in combination with microdialysis. Diabetologia. 2001;44:2171–2179. doi: 10.1007/s001250100026. [DOI] [PubMed] [Google Scholar]
- 79.Peltoniemi P, Lonnroth P, Laine H, et al. Lumped constant for [(18)F] fluorodeoxyglucose in skeletal muscles of obese and nonobese humans. Am J Physiol Endocrinol Metab. 2000;279:E1122–E1130. doi: 10.1152/ajpendo.2000.279.5.E1122. [DOI] [PubMed] [Google Scholar]
- 80.Langer O, Karch R, Müller U, et al. Combined PET and microdialysis for in vivo assessment of intracellular drug pharmacokinetics in humans. J Nucl Med. 2005;46:1835–1841. [PubMed] [Google Scholar]
- 81.Langer O, Mitterhauser M, Brunner M, et al. Synthesis of fluorine-18-labeled ciprofloxacin for PET studies in humans. Nucl Med Biol. 2003;30:285–291. doi: 10.1016/S0969-8051(02)00444-4. [DOI] [PubMed] [Google Scholar]