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

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.

• Authors: Martijn Triesscheijn, Marjan Ruevekamp, Ruud Out, Theo J C Van Berkel, Jan Schellens, Paul Baas, Fiona A Stewart
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 60 Issue 1 Pg. 113-22 (Jun 2007) ISSN: 0344-5704 [Print] Germany
• PMID: 17009028 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Apolipoproteins E
• Lipoproteins
• Lipoproteins, HDL
• Lipoproteins, VLDL
• Mesoporphyrins
• Photosensitizing Agents
• Scarb1 protein, mouse
• Scavenger Receptors, Class B
• temoporfin

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacokinetics, therapeutic use)
• Apolipoproteins E (genetics)
• Area Under Curve
• Carcinoma, Basal Cell (blood, drug therapy, pathology)
• Carcinoma, Squamous Cell (blood, drug therapy, pathology)
• Dose-Response Relationship, Drug
• Female
• Half-Life
• Head and Neck Neoplasms (blood, drug therapy, pathology)
• Humans
• Injections, Intravenous
• Lipoproteins (analysis, blood)
• Lipoproteins, HDL (blood)
• Lipoproteins, VLDL (blood)
• Mesoporphyrins (blood, pharmacokinetics, therapeutic use)
• Mice
• Mice, Inbred BALB C
• Mice, Knockout
• Neoplasms (blood, drug therapy, pathology)
• Photochemotherapy (methods)
• Photosensitizing Agents (administration & dosage, pharmacokinetics, therapeutic use)
• Scavenger Receptors, Class B (genetics)
• Species Specificity
• Tissue Distribution