THE PHARMACOKINETICS OF 8-METHOXYPSORALEN FOLLOWING IV ADMINISTRATION IN HUMANS

1 8-methoxypsoralen (8-MOP) is a naturally occurring photoreactive substance which, in the presence of u.v. light, forms covalent adducts with pyrimidine bases in nucleic acids. For many years, 8-MOP has been used in PUVA therapy for treatment of psoriasis. Recently, the drug has been found to inactivate effectively bacteria spiked into platelet concentrates. The purpose of this study was to determine the pharmacokinetics and safety of 8-MOP administered intravenously in the bactericidal dosage range. 2 Eighteen volunteers were divided into three treatment groups to receive, respectively, 5, 10, and 15 mg 8-MOP infused over 60 min. Frequent arterial samples were gathered, and the blood and plasma were assayed for 8-MOP concentration. The pharmacokinetic parameters were determined by moment and compartmental population analysis, the latter performed with the program NONMEM. Haemodynamics, ventilatory pattern, and subjective effects were recorded throughout the study. 3 The intravenously administered 8-MOP was well tolerated in all individuals, and no acute toxicity was observed. 4 The pharmacokinetics of 8-MOP were best described by a three-compartment mammillary model in which the volumes and clearances were proportional to weight. The mean pharmacokinetic parameters for the plasma concentrations were: V-1 = 0.0451 kg(-1), V-2 = 0.571 kg(-1), V-3 = 0.151 kg(-1), CL(1) (systemic) = 0.0101 kg(-1) min(-1), CL(2) = 0.00671 kg(-1) min(-1), CL(3) = 0.0121 kg(-1) min(-1). The mean pharmaco-kinetic parameters for the blood concentrations were: V-1 = 0.0611 kg(-1), V-2 = 1.151 kg(-1), V-3 = 0.211 kg(-1), CL(1) (systemic) 0.0151 kg(-1) min(-1), CL(2) = 0.0111 kg(-1) min(-1) and CL(3) = 0.0151 kg(-1) min(-1) 5 The plasma pharmacokinetic model described the observations with a median absolute error of 17%, and the blood pharmacokinetic model described the observations with a median absolute error of 18%. Analysis of the relative concentration of 8-MOP between plasma and red blood cells suggested concentration-dependent partitioning. 6 The addition of 7.5 mg 8-MOP to 300 ml platelet concentrate would produce bactericidal concentrations of 25 mu g ml. Simulations based upon our data show that intravenous administration of 7.5 mg over 60 min would result in systemic concentrations of 8-MOP similar to those observed with conventional PUVA therapy. We conclude that the extensive safety history established in PUVA therapy will be applicable to this new application of 8-MOP.