title: The pharmacokinetic behavior of the photosensitizer meso-tetra-hydroxyphenyl-chlorin in mice and men.
abstract: OBJECTIVE
  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.affiliation: Division of Experimental Therapy, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Martijn
authors.initials: M
authors.lastname: Triesscheijn
authors.forename: Marjan
authors.initials: M
authors.lastname: Ruevekamp
authors.forename: Ruud
authors.initials: R
authors.lastname: Out
authors.forename: Theo J C
authors.initials: TJ
authors.lastname: Van Berkel
authors.forename: Jan
authors.initials: J
authors.lastname: Schellens
authors.forename: Paul
authors.initials: P
authors.lastname: Baas
authors.forename: Fiona A
authors.initials: FA
authors.lastname: Stewart
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001057:Apolipoproteins E / Q000235:genetics; D019540:Area Under Curve; D002280:Basal Cell Carcinoma / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006258:Head and Neck Neoplasms / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D007275:Injections, Intravenous; D008074:Lipoproteins / Q000032:analysis / Q000097:blood; D008075:Lipoproteins, HDL / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood; D008652:Mesoporphyrins / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D010778:Photochemotherapy / Q000379:methods; D017319:Photosensitizing Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051122:Scavenger Receptors, Class B / Q000235:genetics; D013045:Species Specificity; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D001057:Apolipoproteins E; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D008079:Lipoproteins, VLDL; D008652:Mesoporphyrins; D017319:Photosensitizing Agents; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; C072269:temoporfin