Mechanisms of photosensitization by phototoxic drugs

https://doi.org/10.1016/S0027-5107(98)00189-4Get rights and content

Introduction

In addition to the direct responses to UVA and UVB exposure, the human system can be subjected to sunlight-mediated effects involving endogenous and exogenous photosensitizers. Prescription medication has been associated with a significant number of adverse photosensitivity effects, many with a close resemblance to sunburn. The molecular mechanisms of photosensitization by drugs are being studied by examining the properties of their photoexcited states, and in terms of free radical and singlet oxygen mediated photooxidation and electron transfer reactions in model biological systems. In general, the generation of an adverse photosensitivity response can be postulated to involve one or more of the pathways shown in Fig. 1.

Since the primary event in any photosensitization process is the absorption of a photon, a critical property of the drug is its absorption spectrum, and the extent of overlap of that spectrum with the sunlight spectrum. The potential for increase in exposure at the shorter wavelength end of the sunlight spectrum (<300 nm) with decrease in the level of stratospheric ozone protection is a cause for concern. The majority of drugs implicated in adverse photosensitivity effects absorb in the UVA spectral region of sunlight. However, there are many more which absorb in the UVB and these have the potential to be activated if there were an increase in sunlight intensity in that region. Although sunscreens will protect the patient, such agents must be properly applied to avoid the danger of drug photosensitization being added to the normal sunburning effect.

One important drug class implicated in photosensitivity responses is the anti-inflammatory group. It is paradoxical that drugs which are prescribed for the relief of inflammation are also implicated in causing an inflammatory side effect with the aid of sunlight. The non-steroidal anti-inflammatory drugs (NSAID) are being more widely used for the treatment of rheumatoid and osteo-arthritis by a steadily `greying' population. One of the concerns is that new formulations for topical application are being released, and many of these are available `over-the-counter' without prescription. There are many photochemically active compounds in this diverse group of drugs and a number of adverse photosensitivity responses have been recorded. One of the most notorious is benoxaprofen which was withdrawn after only a brief release in Europe, following many clearly documented phototoxic reactions. Some of the NSAIDs which are photoactive are shown in Fig. 2.

The following discussion gives a number of examples of the elucidation of the specific mechanisms of action of drug photosensitizers. These examples are representative of several therapeutic classes and include the NSAIDs naproxen and diclofenac, the immunosuppressant azathioprine and the antibacterial agent sulfamethoxazole. Background detail of the fundamental photochemical and photophysical processes leading to the generation of free radicals and singlet oxygen by photoexcited drug molecules has been given elsewhere [1].

Section snippets

Naproxen

The NSAIDs with the 2-arylpropionic acid substituent in their structure, such as naproxen and ketoprofen, have been shown to react in similar fashion through that common grouping. The initial photochemical steps were determined by flash photolysis, a technique for detecting the transients (on a microsecond time scale) formed immediately after absorption of UVR. The data from such experiments on naproxen in aqueous solution at pH 7 are shown in Fig. 3. The transient spectra were identified as

Conclusions

A series of in vitro experiments can be used to elucidate the mechanisms whereby drugs and other exogenous chemicals are potentially able to initiate photosensitivity reactions in humans. In most reactions molecular oxygen is involved, with free radical mechanisms being the dominant type compared to singlet oxygen. However, some examples of electron transfer processes independent of oxygen participation can be demonstrated. The principal question is whether the event(s) initiated by the

First page preview

First page preview
Click to open first page preview

References (12)

There are more references available in the full text version of this article.

Cited by (0)

View full text