The pharmacokinetic behavior of the photosensitizer meso-tetra -hydroxyphenyl -chlorin in mice and men

• Published in: Cancer chemotherapy and pharmacology 2007-06, Vol.60 (1), p.113-122
• Main Authors: TRIESSCHEIJN, Martijn, RUEVEKAMP, Marjan, OUT, Ruud, VAN BERKEL, Theo J. C, SCHELLENS, Jan, BAAS, Paul, STEWART, Fiona A
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Apolipoprotein E; Apolipoproteins E - genetics; Area Under Curve; Biological and medical sciences; Blood plasma; Carcinoma, Basal Cell - blood; Carcinoma, Basal Cell - drug therapy; Carcinoma, Basal Cell - pathology; Carcinoma, Squamous Cell - blood; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - pathology; Cholesterol; Diseases of the skin. Cosmetics; Dose-Response Relationship, Drug; Esters; Female; Half-Life; Head and Neck Neoplasms - blood; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - pathology; High density lipoprotein; Humans; Hydrophobicity; In vivo methods and tests; Injection; Injections, Intravenous; Intravenous administration; Lipid metabolism; Lipoproteins; Lipoproteins - analysis; Lipoproteins - blood; Lipoproteins, HDL - blood; Lipoproteins, VLDL - blood; Medical sciences; Mesoporphyrins - blood; Mesoporphyrins - pharmacokinetics; Mesoporphyrins - therapeutic use; Mice; Mice, Inbred BALB C; Mice, Knockout; Neoplasms - blood; Neoplasms - drug therapy; Neoplasms - pathology; Pharmacokinetics; Pharmacology; Pharmacology. Drug treatments; Photochemotherapy - methods; Photosensitizing Agents - administration & dosage; Photosensitizing Agents - pharmacokinetics; Photosensitizing Agents - therapeutic use; Plasma; Radiotherapy. Instrumental treatment. Physiotherapy. Reeducation. Rehabilitation, orthophony, crenotherapy. Diet therapy and various other treatments (general aspects); Scavenger Receptors, Class B - genetics; Species Specificity; Tissue Distribution
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-006-0356-9

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. Plasma of cancer patients and mice, intravenously injected with mTHPC, was analyzed for total drug content and drug distribution over the lipoprotein fractions. 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. We conclude that neither lipoprotein levels nor cholesterol metabolism affects the pharmacokinetics of mTHPC in plasma.