Abstract
Purpose
Meso-tetra-hydroxyphenyl-chlorin (mTHPC) is a hydrophobic photosensitizer that binds to plasma lipoproteins after intravenous injection. In vitro experiments with human plasma have shown that mTHPC initially binds to an unknown protein and subsequently redistributes to lipoprotein fractions. It has been suggested that this might explain the unusual pharmacokinetic profile of mTHPC humans. In humans, unlike in rodents, reappearance of mTHPC has been reported, resulting in a second plasma peak after intravenous injection. However, previous studies analyzed only limited time points during the first 24 h after injection. Our aim was to determine the pharmacokinetics of mTHPC in detail, and to investigate whether the pharmacokinetic behavior of the drug is affected by binding of mTHPC to lipoproteins in vivo.
Methods
Plasma of cancer patients and mice, intravenously injected with mTHPC, was analyzed for total drug content and drug distribution over the lipoprotein fractions.
Results
Pharmacokinetic profiles of mTHPC in a group of human subjects showed that apparent steady state drug levels were maintained for at least 10 h. Closer examination of individual profiles showed that the initial (5 min) plasma drug levels were on average 86% of the maximal plasma concentration, which occurred at about 5 h after injection. In mice, however, plasma pharmacokinetics were described by a standard bi-exponential decline of the drug concentration. The majority (>58%) of mTHPC injected into both BALB/c nude mice and patients initially bound to the HDL plasma fraction. We extended our study to ApoE −/− mice, with highly elevated lipoprotein levels, and SR-BI −/− mice, which are lacking the main clearance pathway for HDL associated cholesteryl esters, to take into account the differences between lipoprotein levels and clearance in mice and man. Although mTHPC distribution over the lipoproteins changed in these mice, pharmacokinetic profiles of mTHPC remained the same.
Conclusions
We conclude that neither lipoprotein levels nor cholesterol metabolism affects the pharmacokinetics of mTHPC in plasma.
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References
Allison BA, Pritchard PH, Richter AM, Levy JG (1990) The plasma distribution of benzoporphyrin derivative and the effects of plasma lipoproteins on its biodistribution. Photochem Photobiol 52:501–507
Blant SA, Glanzmann TM, Ballini JP, Wagnieres G, Van den Bergh H, Monnier P (2002) Uptake and localisation of mTHPC (Foscan) and its 14C-labelled form in normal and tumour tissues of the hamster squamous cell carcinoma model: a comparative study. Br J Cancer 87:1470–1478
Braichotte D, Savary JF, Glanzmann T, Westermann P, Folli S, Wagnieres G, Monnier P, Van den Bergh H (1995) Clinical pharmacokinetic studies of tetra(meta-hydroxyphenyl)chlorin in squamous cell carcinoma by fluorescence spectroscopy at 2 wavelengths. Int J Cancer 63:198–204
Buchholz J, Kaser-Hotz B, Khan T, Rohrer Bley C, Melzer K, Schwendener RA, Roos M, Walt H (2005) Optimizing photodynamic therapy: in vivo pharmacokinetics of liposomal meta-(tetrahydroxyphenyl)chlorin in feline squamous cell carcinoma. Clin Cancer Res 11:7538–7544
Campbell GA, Bartels KE, Arnold C, Healey T, Cowell RL, Lucroy MD, Ronn AM (2002) Tissue levels, histologic changes and plasma pharmacokinetics of meta-tetra (hydroxyphenyl) chlorin (mTHPC) in the cat. Lasers Med Sci 17:79–85
Cramers P, Ruevekamp M, Oppelaar H, Dalesio O, Baas P, Stewart FA (2003) Foscan uptake and tissue distribution in relation to photodynamic efficacy. Br J Cancer 88:283–290
Glanzmann T, Hadjur C, Zellweger M, Grosiean P, Forrer M, Ballini JP, Monnier P, Van den Bergh H, Lim CK, Wagnieres G (1998) Pharmacokinetics of tetra(m-hydroxyphenyl)chlorin in human plasma and individualized light dosimetry in photodynamic therapy. Photochem Photobiol 67:596–602
Hopkinson HJ, Vernon DI, Brown SB (1999) Identification and partial characterization of an unusual distribution of the photosensitizer meta-tetrahydroxyphenyl chlorin (temoporfin) in human plasma. Photochem Photobiol 69:482–488
Jones HJ, Vernon DI, Brown SB (2003) Photodynamic therapy effect of m-THPC (Foscan) in vivo: correlation with pharmacokinetics. Br J Cancer 89:398–404
Jori G, Reddi E (1993) The role of lipoproteins in the delivery of tumour-targeting photosensitizers. Int J Biochem 25:1369–1375
Kessel D (1986) Porphyrin–lipoprotein association as a factor in porphyrin localization. Cancer Lett 33:183–188
Kessel D (1999) Transport and localisation of m-THPC in vitro. Int J Clin Pract 53:263–267
Kongshaug M, Moan J, Brown SB (1989) The distribution of porphyrins with different tumour localising ability among human plasma proteins. Br J Cancer 59:184–188
Maugain E, Sasnouski S, Zorin V, Merlin JL, Guillemin F, Bezdetnaya L (2004) Foscan-based photodynamic treatment in vivo: correlation between efficacy and Foscan accumulation in tumor, plasma and leukocytes. Oncol Rep 12:639–645
Michael-Titus AT, Whelpton R, Yaqub Z (1995) Binding of temoporfin to the lipoprotein fractions of human serum. Br J Clin Pharmacol 40:594–597
Mitra S, Foster TH (2005) Photophysical parameters, photosensitizer retention and tissue optical properties completely account for the higher photodynamic efficacy of meso-tetra-hydroxyphenyl-chlorin vs photofrin. Photochem Photobiol 81:849–859
Ris HB, Altermatt HJ, Inderbitzi R, Hess R, Nachbur B, Stewart JC, Wang Q, Lim CK, Bonnett R, Berenbaum MC, Althaus U (1991) Photodynamic therapy with chlorins for diffuse malignant mesothelioma: initial clinical results. Br J Cancer 64:1116–1120
Ronn AM, Nouri M, Lofgren LA, Steinberg BM, Westerborn A, Windahl T, Shikowitz MJ, Abramson AL (1996) Human tissue levels and plasma pharmacokinetics of temoporfin (Foscan, mTHPC). Lasers Med Sci 11:267–272
Sasnouski S, Zorin V, Khludeyev I, D’Hallewin MA, Guillemin F, Bezdetnaya L (2005) Investigation of Foscan interactions with plasma proteins. Biochim Biophys Acta 1725:394–402
Triesscheijn M, Ruevekamp M, Aalders M, Baas P, Stewart FA (2005) Outcome of mthpc mediated photodynamic therapy is primarily determined by the vascular response. Photochem Photobiol 81:1161–1167
Whelpton R, Michael-Titus AT, Basra SS, Grahn M (1995) Distribution of temoporfin, a new photosensitizer for the photodynamic therapy of cancer, in a murine tumor model. Photochem Photobiol 61:397–401
Whelpton R, Michael-Titus AT, Jamdar RP, Abdillahi K, Grahn MF (1996) Distribution and excretion of radiolabeled temoporfin in a murine tumor model. Photochem Photobiol 63:885–891
Acknowledgments
This study was supported by the Dutch Cancer Society, Grant NKI 2000–2282.
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Triesscheijn, M., Ruevekamp, M., Out, R. et al. The pharmacokinetic behavior of the photosensitizer meso-tetra-hydroxyphenyl-chlorin in mice and men. Cancer Chemother Pharmacol 60, 113–122 (2007). https://doi.org/10.1007/s00280-006-0356-9
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DOI: https://doi.org/10.1007/s00280-006-0356-9