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Plasma pharmacokinetics and cerebrospinal fluid penetration of hypericin in nonhuman primates.

Abstract：

UNLABELLED:Hypericin, a polycyclic aromatic dianthroquinone, is a natural pigment derived from the plant Hypericum perforatum (St John's Wort). The compound has been synthesized and shown to inhibit the growth of malignant glioma cell lines in vitro via inhibition of protein kinase C. Oral hypericin has entered clinical trials in adults with recurrent malignant glioma. PURPOSE:The present study was performed to characterize the plasma pharmacokinetics (PK) and cerebrospinal fluid (CSF) penetration of hypericin in nonhuman primates. METHODS:Hypericin was administered as an intravenous bolus dose of 2 mg/kg (n = 3) or 5 mg/kg (n = 1). Plasma and CSF (ventricular or lumbar) were sampled prior to administration and at frequent intervals for up to 50 h after administration of the drug. Hypericin concentrations in plasma and CSF were determined using a specific reverse-phase HPLC assay. RESULTS:Mean peak plasma concentration of hypericin following the 2 mg/kg dose was 142 +/- 45 microM. Elimination of hypericin from plasma was biexponential, with an average alpha half-life of 2.8 +/- 0.3 h and average terminal half-life of 26 +/- 14 h. CONCLUSIONS:The 2 mg/kg dose in the nonhuman primate was sufficient to maintain plasma concentrations above 10 microM (the in vitro concentration required for growth inhibition of human glioma cell lines) for up to 12 h. No hypericin was detected in the CSF of any animal (lower limit of detection 0.1 microM); the CSF penetration is therefore less than 1%. A severe dose-limiting photosensitivity skin rash was seen at the 5 mg/kg dose level.

journal_name

Cancer Chemother Pharmacol

journal_title

Cancer chemotherapy and pharmacology

authors

Fox E,Murphy RF,McCully CL,Adamson PC

doi

10.1007/s002800000188

keywords:

subject

Has Abstract

pub_date

2001-01-01 00:00:00

pages

41-4

issue

1

eissn

0344-5704

issn

1432-0843

journal_volume

47

pub_type

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