The combination treatment regimen of psoralen (P) and
ultraviolet radiation of 320-400 nm wavelength commonly referred to as UVA is
known by the acronym, PUVA. Skin reactivity to UVA (320-400 nm) radiation is
markedly enhanced by the ingestion of methoxsalen. In a well controlled
bioavailability study, Oxsoralen-Ultra Capsules reached peak drug levels in the
blood of test subjects between 0.5 and 4 hours (Mean = 1.8 hours) as compared
to between 1.5 and 6 hours (Mean = 3.0 hours) for regular Oxsoralen when administered
with 8 ounces of milk. Peak drug levels were 2 to 3 fold greater when the
overall extent of drug absorption was approximately two fold greater for
Oxsoralen-Ultra Capsules as compared to regular Oxsoralen Capsules. Detectable
methoxsalen levels were observed up to 12 hours post dose. The drug half-life
is approximately 2 hours. Photosensitivity studies demonstrate a shorter time
of peak photosensitivity of 1.5 to 2.1 hours vs. 3.9 to 4.25 hours for regular
Oxsoralen capsules. In addition, the mean minimal erythema dose (MED), J/cm²,
for the Oxsoralen-Ultra Capsules is substantially less than that required for
regular Oxsoralen Capsules (Levins et al., 1984 and private communication1).
Methoxsalen is reversibly bound to serum albumin and is
also preferentially taken up by epidermal cells (Artuc et al., 19792).
At a dose which is six times larger than that used in humans, it induces mixed
function oxidases in the liver of mice (Mandula et al., 19783). In
both mice and man, methoxsalen is rapidly metabolized. Approximately 95% of the
drug is excreted as a series of metabolites in the urine within 24 hours
(Pathak et al., 19774). The exact mechanism of action of methoxsalen
with the epidermal melanocytes and keratinocytes is not known. The best known
biochemical reaction of methoxsalen is with DNA. Methoxsalen, upon
photoactivation, conjugates and forms covalent bonds with DNA which leads to
the formation of both monofunctional (addition to a single strand of DNA) and
bifunctional (crosslinking of psoralen to both strands of DNA) adducts (Dall'
Acqua et al., 19715; Cole, 19706; Musajo et al., 19747;
Dall' Acqua et al., 19798). Reactions with proteins have also been
described (Yoshikawa, et al., 19799).
Methoxsalen acts as a photosensitizer. Administration of
the drug and subsequent exposure to UVA can lead to cell injury. Orally
administered methoxsalen reaches the skin via the blood and UVA penetrates well
into the skin. If sufficient cell injury occurs in the skin, an inflammatory
reaction occurs. The most obvious manifestation of this reaction is delayed
erythema, which may not begin for several hours and peaks at 48-72 hours. The
inflammation is followed, over several days to weeks, by repair which is
manifested by increased melanization of the epidermis and thickening of the
stratum corneum. The mechanisms of therapy are not known. In the treatment of
psoriasis, the mechanism is most often assumed to be DNA photodamage and
resulting decrease in cell proliferation but other vascular, leukocyte, or cell
regulatory mechanisms may also be playing some role. Psoriasis is a
hyper-proliferative disorder and other agents known to be therapeutic for
psoriasis are known to inhibit DNA synthesis.
1. Levins, P.C., Gange, R.W., Momtaz-T,K., Parrish, J.A.,
and Fitzpatrick, T.B.: A New Liquid Formulation of 8-Methoxypsoralen:
Bioactivity and Effect of Diet: JID, 82, No. 2, pp. 185-187 (1984) and private
2. Artuc,M., Stuettgen, G., Schalla, W., Schaefer, H.,
and Gazith, J.: Reversible binding of 5-and 8- methoxypsoralen to human serum
proteins (albumin) and to epidermis in vitro: Brit. J. Dermat. 101, pp. 669-677
3. Mandula, B.B., Pathak, M.A., Nakayama, T., and
Davidson, S.J.: Induction of mixed-function oxidases in mouse liver by psoralens.,
Ibid, 99, pp. 687-692 (1978).
4. Pathak, M.A., Fitzpatrick, T.B., Parrish, J.A.:
PSORIASIS, Proceedings of the Second International Symposium. Edited by E.M.
Farber, A.J. Cox, Yorke Medical Books, pp. 262-265 (1977).
5. Dall'Acqua, F., Marciani, S., Ciavatta, L.,
Rodighiero, G.: Formation of interstrand cross-linkings in the photoreactions
between furocoumarins and DNA; Z Naturforsch (B), 26, pp. 561-569 (1971).
6. Cole, R.S.: Light-induced cross-linkings of DNA in the
presence of a furocoumarin (psoralen), Biochem.Biophys. Acta, 217, pp. 30-39
7. Musajo, L., Rodighiero, G., Caporale, G., Dall'Acqua,
F., Marciani, S., Bordin, F., Baccichetti, F., Bevilacqua, R.: Photoreactions
between Skin-Photosensitizing Furocoumarins and Nucleic Acids, Sunlight and
Man; Normal and Abnormal Photobiologic Responses. Edited by M.A. Pathak, L.C.
Harber, M. Seiji et al. University of Tokyo Press, pp. 369-387 (1974).
8. Dall'Acqua, F., Vedaldi, D., Bordin, F., and Rodighiero,
G.: New studies in the interaction between 8-methoxypsoralen and DNA in vitro;
JID, 73, pp. 191-197 (1979).
9. Yoshikawa, K., Mori, N., Sakakibara, S., Mizuno, N.,
Song, P.: Photo Conjugation of 8- methoxypsoralen with Proteins; Photochem.
& Photobiol. 29, pp. 1127-1133 (1979).