The pharmacokinetic behavior of the photosensitizer meso-tetra-hydroxyphenyl-chlorin in mice and men
| Autor: | Martijn Triesscheijn, Theo J.C. Van Berkel, Marjan Ruevekamp, Ruud Out, Jan H.M. Schellens, Paul Baas, Fiona A. Stewart |
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| Rok vydání: | 2006 |
| Předmět: |
Apolipoprotein E
Cancer Research Lipoproteins Antineoplastic Agents Pharmacology Lipoproteins VLDL Toxicology Temoporfin chemistry.chemical_compound Mice Apolipoproteins E Pharmacokinetics Species Specificity In vivo Neoplasms Distribution (pharmacology) Animals Humans Pharmacology (medical) Photosensitizer Tissue Distribution Mice Knockout Mice Inbred BALB C Photosensitizing Agents Dose-Response Relationship Drug Scavenger Receptors Class B In vitro Oncology Biochemistry chemistry Mesoporphyrins Photochemotherapy Carcinoma Basal Cell Head and Neck Neoplasms Area Under Curve Injections Intravenous Carcinoma Squamous Cell lipids (amino acids peptides and proteins) Female Lipoproteins HDL Lipoprotein Half-Life |
| Zdroj: | Cancer chemotherapy and pharmacology. 60(1) |
| ISSN: | 0344-5704 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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