Photosensitive drug eruption induced by flutamide

ARTICLE

Flutamide (FLU; 2-metyl-N-[4-nitro-3-8-trifluorometyl-9 phenyl] propamide; molecular weight, 276.22; half-life, 1.4 hours) (Fig. 1) is a non-steroidal anti-androgen commonly used for the treatment of prostatic carcinoma [1-3]. This drug was first brought onto the market in 1987, and has been used in Japan since 1994. To our knowledge, there are only two reports in the English literature describing photoallergic reaction induced by FLU [4, 5]. We report another case of a photosensitive eruption induced by FLU with some investigations on its reactivity to ultraviolet A light (UVA).

Report of a case

A 68-year-old Japanese man was referred to our clinic on May 8, 1997. He had been treated with 375 mg of FLU daily for prostatic carcinoma since March 1997. He had been suffering from a pruritic, scaly, and erythematous eruption over sun-exposed areas such as the face, neck, dorsa of both hands and V-area of chest for the previous ten days (Fig. 2). Results of the following laboratory tests were normal or negative: complete blood cell count, differential leukocyte count, blood smear, blood chemistry studies, lipid levels, antinuclear antibodies, and urinalysis. Since photosensitivity was highly suspected based on the clinical features, he was treated with topical applications of corticosteroid and advised to use sun-screen agents. The response was good. However, skin lesions recurred at the end of May upon exposure to sunlight. Therefore, the administration of FLU was discontinued on May 30.

Minimal erythema doses (MED) with UVA and UVB were measured during administration and seventeen days after the cessation of FLU. Black light (FL32SBL) emitting UVA ranging from 320 to 400 nm with peak emission at 365 nm and a sunlamp (FL20SE30) emitting UVB ranging from 280 to 320 nm with peak emission at 305 nm were purchased from Toshiba Electric Co. (Tokyo, Japan). With a UV radiometer (Eisai Co., Tokyo, Japan), the energy output of fourteen, 32 W tubes of black light at a distance of 30 cm was 6.8 mW/cm² at 365 nm and 0.21 mW/cm² at 305 nm, and that of seven 20 W tubes of the sunlamp was 1.4 mW/cm² at 305 nm and less than 0.01 mW/cm² at 365 nm, respectively. MEDs measured under administration of FLU were 2 J/cm² and 42 mJ/cm² with UVA and UVB, respectively (Fig. 3). MEDs after cessation of FLU rose to 16 J/cm² with UVA and 42 mJ/cm² with UVB. Thus, the patient was sensitive to UVA when receiving FLU.

A biopsy specimen obtained, after informed consent, from a fully reacted, UVA-irradiated site on the back showed liquefaction degeneration of basal cells with upper-dermal infiltration of lymphocytes, some of which infiltrated into the epidermis (Fig. 4). Therefore, the provoked site histologically exhibited the lichenoid tissue reaction.

A diagnosis of photosensitive drug eruption induced by FLU was thus made. There was no recurrence after withdrawal of the drug.

Absorption spectra of non- and UVA-irradiated FLU and a photocoupling study between FLU and protein.

To examine the UVA-photostability of flutamide, the absorption spectra were measured with a spectrometer (UVIDEC-660; Japan Spectroscopic Co., Tokyo, Japan) as previously reported [6]. FLU (kindly donated by Nippon Kayaku Co., Tokyo, Japan) was dissolved in absolute ethanol at 1 mg/ml and diluted to 40 µg/ml in phosphate-buffered saline (PBS; pH 7.4). The absorption peak of non-irradiated FLU was 303 nm (Fig. 5). The solutions were placed in plastic dishes (Falcon 3001, Becton Dickinson, Oxnard, CA, USA) and irradiated with three black light tubes at a distance of 20 cm, through a pane of 3 mm thick glass to ensure that no radiation below 320 nm reached the solutions. Under these conditions, the radiation that reached the solution was 2.2 mW/cm² at 365 nm. Neither the peak nor its absorbance was changed by UVA-exposure at energy levels of 0.40, 1.33, or 3.33 J/cm² (Fig. 5), suggesting that FLU is not photodegraded by UVA.

To examine covalent photocoupling of FLU with protein, equal volumes of FLU (30 nM in PBS) and bovine serum albumin (BSA, 10 nM in PBS) were mixed, placed in a plastic dish, and irradiated with black light (4 J/cm² at 365 nm). The solution was chromatographed on Sephadex LH-20 (Pharmacia, Uppsala, Sweden) and equilibrated with 20% ethanolic phosphate buffer, as described previously [6]. When monitored at absorbance 305 nm for FLU and at 280 nm for BSA, FLU was not eluted in the early fractions which contained BSA. This indicated that FLU was not covalently linked to BSA by irradiation with UVA.

Discussion

Our patient showed a lichenoid eruption on sun-exposed areas. Under treatment with FLU, the MED with UVA was reduced to 2 J/cm² at 365 nm. After withdrawal of FLU, it recovered to over 16 J/cm² without changing the response to UVB. These observations clearly indicated that he had photosensitivity induced by FLU. Concerning photoallergic reactions induced by FLU, there are only two reports in the English literature [4, 5] and two more reports written in other languages [7, 8]. All these patients but one showed positive phototests. The former two reports showed papulovesicular erythema as a clinical feature and an acute eczematous reaction on histology [4, 5]. Since the eruption was strongly provoked by low doses of UVA and the histology demonstrated a lichenoid tissue reaction [9], in our patient FLU photosensitivity seemed to be induced by a photoallergic mechanism. The peak absorption of FLU was in the UVB range. This is in accordance with the concept that the action spectrum in photoallergic responses is longer than the absorption spectrum [10].

As we previously reported, some photoallergic drugs such as afloqualone and fluoroquinolones are known to induce a photodistributed, lichenoid eruption and to serve as photohaptens, which covalently photobind to protein on exposure to UVA upon photodegradation [6, 11, 12]. However, the absorbance of FLU was not changed upon irradiation, and no photocoupling was found with BSA. Thus, FLU is rather photostable and has no photohaptenic properties. Recently, Schnyder et al. reported a drug that is covalently bound to proteins after intracellular drug metabolism [13]. Since FLU exists as an active metabolite, hydroxy-flutamide, in the plasma, it is possible that this metabolite has the potential to work as a photohapten when effectively irradiated in patients. Alternatively, photosensitivity to FLU may be evoked by an, as yet, uncharacterized, non-haptenic mechanism, such as abrogation of the immunologic tolerance of self-reactive T cells in the UVA-exposed skin, leading to the lichenoid tissue reaction.

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