5,8-Dihydroxypsoralen

Disposition of 8-methoxypsoralen in the rat: methodology for measurement, dose-dependent pharmacokinetics, tissue distribution and identification of metabolites.[Pubmed:3944766]

J Pharmacol Exp Ther. 1986 Feb;236(2):364-73.

The pharmacokinetics and metabolism of 8-methoxypsoralen (8-MOP) were measured in the catheterized rat after a single i.v. dose. Blood samples were collected serially and analyzed using a sensitive and specific assay for [14C]-8-MOP. Total body clearance of 8-MOP was 7.3, 3.9, 1.7, 1.0, 0.78 and 0.42 liters/kg/hr at doses of 0.2, 1.0, 2.5, 5.0, 10 and 20 mg/kg, respectively. The decline in total body clearance indicates that elimination of 8-MOP is dose-dependent in the rat. After i.v. administration of 10 mg/kg of 8-MOP, 71 and 26% of the dose was recovered within 72 hr in the urine and feces, respectively. Unchanged 8-MOP accounted for less than 1% of the excreted radioactivity. In tissue distribution studies at 0.5, 2 and 5 hr after i.v. administration, 8-MOP distributed rapidly to all tissues and concentrated in the fat and kidneys. The concentration of 8-MOP in the skin was 0.4 to 0.6 times that in the blood. Eleven metabolites of 8-MOP were detected in the urine. The metabolites identified after enzymatic hydrolysis were 8-hydroxypsoralen; 5-hydroxy-8-methoxypsoralen; 5,8-Dihydroxypsoralen; 5,8-dioxopsoralen; 6-(7-hydroxy-8-methoxycoumaryl)-acetic acid and 8-MOP (formed by ring closure of a coumaric acid metabolite). Thus, these studies indicate that 8-MOP is metabolized in the rat by 1) O-demethylation; 2) hydroxylation at position 5; 3) hydrolysis of the lactone ring and 4) oxidation of the furan ring, a pathway already confirmed in insects, dogs and humans.

Disposition of 8-methoxypsoralen in the rat. Induction of metabolism in vivo and in vitro and identification of urinary metabolites by thermospray mass spectrometry.[Pubmed:2886306]

Drug Metab Dispos. 1987 May-Jun;15(3):318-28.

The pharmacokinetics and metabolism of 8-methoxypsoralen (8-MOP) were measured in the catheterized rat after pretreatment for 3 days with phenobarbital (PB), beta-naphthoflavone (BNF), 8-MOP, or vehicle. After an iv injection of 10 mg/kg of [14C]8-MOP, timed blood samples were collected and analyzed using a sensitive and specific assay for [14C]8-MOP. Total body clearance of 8-MOP increased from 0.55 +/- 0.06 liter/kg/hr in control rats to 5.6 +/- 0.4, 2.7 +/- 0.4, and 1.2 +/- 0.0 liters/kg/hr in rats pretreated with BNF, PB, and 8-MOP, respectively, indicating that all three compounds are inducers of 8-MOP metabolism. The pattern of urinary metabolites was altered by the enzyme inducers. The urinary excretion of the sulfate conjugate of 5-hydroxy-8-methoxypsoralen was increased from 10 to 40% of the dose after pretreatment with PB. This intact conjugate was identified using thermospray and fast atom bombardment mass spectrometry. Pretreatment with 8-MOP and BNF increased 2- and 3-fold, respectively, the urinary excretion of a labile sulfate conjugate of 5,8-Dihydroxypsoralen. Metabolism of 8-MOP was demonstrated in the 9000 g supernatant and microsomes of rat liver and shown to be inducible by pretreatment of rats with BNF, PB, and 8-MOP. 8-MOP was metabolized in incubations with liver microsomes at rates of 0.22 +/- 0.06, 0.38 +/- 0.06, 0.78 +/- 0.07, and 0.91 +/- 0.03 nmol/min/mg of protein for vehicle, 8-MOP-, PB-, and BNF-pretreated rats, respectively. Results of our investigation indicate that the success of therapy with 8-MOP may be influenced by pharmacokinetic interactions with other drugs.

Fate of [(14)C]xanthotoxin (8-methoxypsoralen) in laying hens and a lactating goat.[Pubmed:24254913]

J Chem Ecol. 1992 Feb;18(2):253-70.

The metabolism of xanthotoxin, a naturally occurring furanocoumarin photosensitizer, was studied in laying hens and a lactating goat treated with single oral doses equivalent to 10 mg xanthotoxin/kg of body weight. Within 48 h, essentially all of the administered radiocarbon was eliminated in the excreta of the laying hens, while in the goat 92% and 3% were excreted in the urine and feces, respectively. Radiocarbon residues in the milk, egg white, and egg yolk were low. Xanthotoxin, 8-hydroxypsoralen (xanthotoxol), 6-(7-hydroxy-8-methoxycoumaryl)-acetic acid (HCA) and 6-(7-hydroxy-8-methoxycoumaryl)-hydroxyacetic acid (HCHA) were identified in the excreta of laying hens. In the goat, xanthotoxin was metabolized to HCA, HCHA, xanthotoxol, 5,8-Dihydroxypsoralen, psoralenquinone, 5-hydroxy-8-methoxy-psoralen and 3[5-(6-hydroxy-7-methoxybenzofuryl)]-propanoic acid. Thus, identified metabolites in one or both of these species arose throughO-demethylation, oxidative cleavage of the furan ring, hydroxylation, reduction, oxidation, and hydrolysis of the lactone ring.