Monitoring of 8-methoxypsoralen during extracorporeal photochemotherapy: evidence for a "first-dose" effect.

Therapeutic monitoring of 8-methoxypsoralen (8-MOP) was studied in 12 patients (age range 43-85 years, weight range 48-76 kg) treated for Sezary's syndrome by extracorporeal photochemotherapy (ECP) for 14-41 months. Before the beginning of each ECP cycle (2 sessions on consecutive days at about 4-week intervals), a blood sample was drawn to determine the 8-MOP plasma concentration 2 h after drug ingestion. Plasma 8-MOP levels were measured using a high-performance liquid chromatography method with spectrophotometric detection. Monitoring parameters (dose, 2-h plasma 8-MOP concentration) showed important interindividual and intraindividual variations. The 8-MOP dose ranged from 0.57 to 1.04 mg/kg. Intraindividual variations of 2-h 8-MOP levels ranged from 21% to 75%. Of the 652 measurements, 13% were < 100 ng/ml, the therapeutic threshold for effective ECP; in three of the seven patients, increasing the dose obtained levels exceeding the therapeutic threshold, i.e, the absorption was not saturable. Orthogonal regression analysis between plasma 8-MOP concentrations measured in two consecutive ECP sessions showed a first-dose effect: the 2-h plasma 8-MOP concentration was significantly lower after the first administration than after the second (approximately 1.26-fold). Because 8-MOP has been proven to be a potent suicide inhibitor of drug metabolism in rats and humans, it is possible that 8-MOP had an inhibitory effect on its own metabolism within the therapeutic dose range for ECP, which would explain in part the inter- and intraindividual variability in 8-MOP kinetics and first-dose effect.

[1]  F. Trautinger,et al.  Parenteral administration of 8-methoxypsoralen in photopheresis. , 1993, Journal of the American Academy of Dermatology.

[2]  H. Angelo,et al.  The influence of food on 8‐methoxypsoralen serum concentration and minimal phototoxic dose , 1992, The British journal of dermatology.

[3]  F. Meyer,et al.  Variability of serum levels for three oral 8-methoxypsoralen brands. , 1992, Photodermatology, photoimmunology & photomedicine.

[4]  G. Briand,et al.  Variation in 8-methoxypsoralen profiles during long-term psoralen plus ultraviolet A therapy and correlations between serum 8-methoxypsoralen levels and chromametric parameters. , 1991, Photodermatology, photoimmunology & photomedicine.

[5]  U. Haustein,et al.  8‐Methoxypsoralen Serum Levels in Poor Responders to Photochemotherapy , 1991, International journal of dermatology.

[6]  F. Meyer,et al.  [Pharmacokinetic comparison of 3 8-methoxypsoralen preparations and clinical aspects]. , 1990, Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete.

[7]  F. Gasparro,et al.  Molecular aspects of extracorporeal photochemotherapy. , 1989, The Yale journal of biology and medicine.

[8]  P. Cheney,et al.  Methoxsalen is a potent inhibitor of the metabolism of caffeine in humans , 1987, Clinical pharmacology and therapeutics.

[9]  D. Mays,et al.  Inhibition and induction of drug biotransformation in vivo by 8-methoxypsoralen: studies of caffeine, phenytoin and hexobarbital metabolism in the rat. , 1987, The Journal of pharmacology and experimental therapeutics.

[10]  S. Unger,et al.  Disposition of 8-methoxypsoralen in the rat. Induction of metabolism in vivo and in vitro and identification of urinary metabolites by thermospray mass spectrometry. , 1987, Drug metabolism and disposition: the biological fate of chemicals.

[11]  D. Pessayre,et al.  Inactivation of human liver cytochrome P-450 by the drug methoxsalen and other psoralen derivatives. , 1987, Biochemical pharmacology.

[12]  K Wolff,et al.  Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy. Preliminary results. , 1987, The New England journal of medicine.

[13]  F. Wolff,et al.  Intraindividual and Interindividual variability in 8‐methoxypsoralen kinetics and effect in psoriatic patients , 1983, Clinical pharmacology and therapeutics.

[14]  P. Prognon,et al.  [Quantitative determination of 5-methoxypsoralen in plasma by liquid chromatography and spectrofluorometric detection]. , 1983, Journal of chromatography.

[15]  F. Koss,et al.  The use of stable isotopes to prove the saturable first-pass effect of methoxsalen. , 1980, Biomedical mass spectrometry.

[16]  P. Song,et al.  PHOTOCHEMISTRY AND PHOTOBIOLOGY OF PSORALENS , 1979, Photochemistry and photobiology.

[17]  M. Ehrnebo,et al.  Effect of food on kinetics of 8‐methoxsalen , 1979, Clinical pharmacology and therapeutics.

[18]  J. Parrish,et al.  Oral methoxsalen photochemotherapy of mycosis fungoides , 1976, Cancer.

[19]  F. Wolff,et al.  Clinical Pharmacokinetics of Methoxsalen and Other Psoralens , 1986, Clinical pharmacokinetics.

[20]  P. Prognon,et al.  Dosage du méthoxy-5 psoralène dans le plasma par chromatographie en phase liquide et detection spectrofluorimétrique , 1983 .