Percutaneous penetration of 5-methoxypsoralen in rhesus monkeys.

OBJECTIVE AND DESIGN: 5-methoxypsoralen (bergapten) has been used in the treatment of psoriasis and vitiligo, and as a sun tanning accelerator. While low plasma concentrations have previously been detected, there is no data on its dermatopharmacokinetics. MATERIALS AND METHODS: Three rhesus monkeys were used as a model for human skin. [14C]-5-methoxypsoralen, as a parenteral excretion control, was injected in propylene glycol with an activity of 1.12 uCi/ml at a concentration of 80 mcg/ml and urine was collected at 4, 8, 12, 24h, and then daily for a total of 6 days. [14C]-5-methoxypsoralen was then applied topically in acetone with a dose of 1.19 mc (72 mcg) and urine was collected at 4 and 24h and then daily for a total of 7 days. The amount excreted was corrected for the previously determined parenteral excretion kinetics. RESULTS: Intramuscular [14C]-5-methoxypsoralen had an average of 71.87±7.77% of excretion and percutaneously applied [14C]-5-methoxypsoralen had an average of 58.4±11.8% of excretion. CONCLUSION: A high percentage of the administered 5-methoxypsoralen was absorbed. This provides a foundation of methodology to evaluate the efficacy of other delivery vehicles for 5-methoxypsoralen and serves as part of its dermatotoxic profile.

Inhibition of caffeine metabolism by 5-methoxypsoralen in patients with psoriasis.

Eight patients with psoriasis were given 200 mg caffeine orally with or without 1.2 mg kg-1 of 5-methoxypsoralen. Blood and urine samples were collected over a 2-day period. During 5-methoxypsoralen coadministration, the apparent volume of distribution of caffeine remained unchanged, but oral clearance (CLp.o.) decreased from 9.5 +/- 3.8 (mean +/- s.d.) to 3.2 +/- 0.51 h-1 (P < 0.01). The area under the plasma concentration-time curve (AUC) increased from 24 +/- 9 to 73 +/- 29 mg 1(-1) h (P < 0.001). This decrease in CLp.o. with increased AUC was consistent with a CYP1A2-dependent inhibition of caffeine N-demethylation which was further supported by significant decreases in the (AFMU+1U+1X)/17U and (AFMU+1U+1X)/17X urinary metabolic ratios.

Toxicity of 8-methoxypsoralen in cynomolgous monkeys (Macaca fascicularis).

Male and female cynomolgous monkeys were administered 0, 2, 6 or 18 mg/kg 8-methoxypsoralen (8-MOP) 3 times a week orally for 26 consecutive weeks. Dose-dependent emesis was the most sensitive indicator of 8-MOP toxicity. The lowest dose to elicit emesis was 3 x 6 mg/kg/week of 8-MOP. Among the histological findings proliferation of Kupffer cells was the only recurring observation. However, these finding as well as some hematological and serum electrolyte changes lacked a dose-response relationship. In the highest dosage group one female monkey was found in moribund condition on the 39th day of the study and was killed. Histopathological evidence indicated beginning shock as the cause of the rapidly deteriorating health of the monkey. Similar to effects in man and rats, 8-MOP displayed nonlinear pharmacokinetics in the cynomolgous monkey, saturation occurring between 3 x 2 and 3 x 6 mg/kg/week. Increased clearance of 8-MOP in the lowest dosage group after 26 test weeks was attributed to a combination of enzyme induction and saturable first pass effect. Since the plasma profile of 8-MOP at the lowest dose (3 x 2 mg/kg/week) in cynomolgous monkeys closely resembles that in humans after therapeutic doses (0.4-0.6 mg/kg) and because of other similarities (vomiting as earliest sign of toxicity, saturable first pass effect), it is reasonable to assume that chronic toxicity of 8-MOP as defined in this study is quite predictive for man.

Fate of [14C]xanthotoxin (8-methoxypsoralen) in a goat and in bovine ruminal fluid.

A lactating Nubian goat was treated with [14C]xanthotoxin, a photosensitizing psoralen that occurs naturally in some phototoxic range plants, as a single oral dose equivalent to 10.0 mg of xanthotoxin/kg of body weight. The radiochemical was rapidly absorbed, metabolized, and excreted. Although expired air was not monitored for the presence of volatile radiocarbon, the data indicated that greater than 50% of the administered [14C]xanthotoxin was metabolized by cleavage of the O-[14C]methyl moiety, with subsequent loss of the label as, presumably, [14C]CO2. Studies with bovine ruminal fluid in vitro indicated that cleavage of the O-methyl moiety of xanthotoxin could occur rapidly in the rumen. In the goat, nonmetabolized xanthotoxin was not excreted in urine, and of several metabolites in urine extracts, 3 were identified as resulting from opening of the furan or lactone ring. Only about 2% of the dose was recovered in the feces, and this consisted mainly of unmetabolized xanthotoxin. Although appreciable amounts of radiocarbon were secreted into milk, this radiocarbon was not in the form of xanthotoxin or any identifiable metabolites. The radiocarbon in milk likely resulted from the biosynthetic incorporation of [14C]CO2 into normal milk components.

GLC determination of methoxsalen in human serum and urine.

A simple, sensitive and specific GLC method for the quantitation of methoxsalen in human serum and urine is described. The procedure involves chloroformic extraction of the active ingredient and the internal standard, trioxsalen, followed by GLC determination, using flame ionization detector and 3% OV on a Gas chromosorb W column. Sensitivity was 0.1 microgram/ml and 0.2 microgram/ml for serum and urine, respectively. Methoxsalen contents of serum of rats treated with this drug are reported.

Serum and urine concentrations of 5-methoxypsoralen after oral administration.

Serum and urine concentrations were measured after oral administration of 5-methoxypsoralen (0.6 mg/kg or I.2 mg/kg) to psoriasis patients. A dose of 0.6 mg/kg resulted in low serum concentrations, but after I.2 mg/kg, much higher serum concentrations were reached. There was much individual variation in the time required for reaching peak serum levels. Minute amounts of unchanged 5-methoxypsoralen were excreted in urine. Much larger amounts were excreted as conjugates.

The metabolism of 8-methoxypsoralen in man.

8-Methoxypsoralen is metabolized rapidly and completely in man. Most of the metabolites presently known have their origin in a metabolic attack on the furan moiety yielding an aryl-diol and aryl-acetic-acid and are excreted as conjugates.

The metabolism of 14C-methoxsalen by the dog.

Single doses of 14C-methoxsalen (5 mg/kg) were administered iv to three dogs. Almost as much administered radioactivity was excreted in the feces as in the urine, suggesting that biliary secretion of metabolites was an important route of excretion. 14C-Methoxsalen disappeared rapidly from plasma, although plasma levels of radioactivity persisted for 5 weeks after drug administration. Evidence was obtained which suggested that the persistent plasma radioactivity was due to a metabolite bound to plasma protein. Four urinary metabolites were isolated. Three of the metabolites resulted from opening of the furan ring; these are 7-hydroxy-8-methoxy-2-oxo-2H-1-benzopyran-6-acetic acid (A), alpha,7-dihydroxy-8-methoxy-2-oxo-2H-1-benzopyran-6-acetic acid (B), and an unknown conjugate of A at the 7-hydroxy position. The fourth metabolite, formed by opening of the pyrone ring, is an unknown conjugate of (Z)-3-(6-hydroxy-7-methoxybenzofuran-5-yl)-2-propenoic acid.