Photochemical Reactions Involved in the Phototoxicity of the Anticonvulsant and Antidepressant Drug Lamotrigine (Lamictal^®)

Abstract

Lamotrigine (LTG) [3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine], an anticonvulsant and antidepressant drug Lamictal, produces a (photo)toxic response in some patients. LTG absorbs UV light, generating singlet oxygen (1O2) with a quantum yield of 0.22 in CH2Cl2, 0.11 in MeCN and 0.01 in D2O. A small production of superoxide radical anion was also detected in acetonitrile. Thus, LTG is a moderate photosensitizer producing phototoxicity and oxidizing linoleic acid. LTG is a weak 1O2 quencher (k(q) = 3.2 x 10(5) M(-1) s(-1) in MeCN), but its photodecomposition products in dimethyl sulfoxide (DMSO) quenched 1O2 very efficiently. Upon intense UV irradiation from a xenon lamp, LTG was photobleached rapidly in DMSO and slowly in acetonitrile, alcohol and water. The rate increased significantly when laser pulses at 266 nm were employed. The photobleaching products generated 1O2 twice as strongly as LTG. Photobleaching was usually accompanied by the release of chloride anions, which increased in the presence of ascorbic acid. This suggests the formation of aryl radicals via dechlorination, a process which may be responsible for the photoallergic response observed in some patients. Our results demonstrate that LTG is a moderate generator of 1O2 prone to photodechlorination, especially in a reducing environment, which can contribute to the reported phototoxicity of LTG.

Photoinduced electron transfer photodegradation of photosensitive diuretic drug-xipamide

“…Mechanistic pathway of the formation of photoproduct 3. and DMA radical cation and in subsequent step XIP radical anion on hydrolysis yield photoproduct 2 by loosing ammonia (Scheme 2) similarly when the XIP was irradiated in presence of electron acceptor 1,4-dicyanonaphthalene (DCN), XIP reaches in excited state and in excited state XIP donate an electron to DCN and form XIP radical cation and DCN radical anion and in next step XIP radical cation on hydrolysis yield photoproduct 3 by the substitution of chlorine by hydroxyl group and by back electron transfer (Scheme 3). To conclude, the present results have shown that in presence of both electron acceptor and donor, drug undergoes photodegradation to yield 2-choloro-5-((2, 6-dimethylphenyl)carbamoyl)-4-hydroxybenzenesulfonic and 4-hydroxy-N-(2,6-dimethylphenyl)-2-hydroxy-5-sulfamoylbenzamide as main photodegradation products through photoinduced intermolecular electron transfer mechanism and from the above study it is clearly indicated that during the fragmentation of xipamide in presence of both electron donor and acceptor radical ions are generated and it is a well known fact that radical ion is responsible for phototoxicity [28,29]. So the phototoxicity of xipamide may possible due to these radical ions; hence the present study may find its significance in rationalizing the phototoxicity of the xipamide.…”

Photodistributed toxic epidermal necrolysis in association with lamotrigine and tanning bed exposure

“…Lamotrigine accumulates in both the eyes and skin and undergoes slow photodegradation, releasing chloride anions and free radicals, which may modify the proteins and contribute to phototoxic responses. 8 It is plausible to draw a causal relationship between a phototoxic metabolite of lamotrigine and the development of photodistributed TEN. It is unknown whether lamotrigine itself or its phototoxic metabolites are more potent in the stimulation and progression of SJS/TEN.…”

Use of antiepileptic drugs and risk of skin cancer: A nationwide case-control study

“…Thus, the following AEDs were included: Carbamazepine, clonazepam, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, pregabalin, topiramate, and valproic acid. Of these, AEDs with potential photosensitizing properties were identified from drug labels (19-22), a clinical database of druginduced skin eruptions (8), book chapters or reviews on photosensitizing drugs (23)(24)(25)(26), animal tests (27), clinical tests (28)(29)(30), and photochemical properties (31,32). On this basis, we classified carbamazepine, gabapentin, lamotrigine, oxcarbazepine, phenobarbital, phenytoin, pregabalin, topiramate, and valproic acid as photosensitizing.…”

“…First, lamotrigine and carbamazepine probably increase the skin's susceptibility to sunlight more than other AEDs. These two AEDs are reported to induce photosensitivity reactions in randomized controlled trials (19,20), to induce photosensitivity in clinical tests (28)(29)(30), and to have photochemical properties that suggest photosensitizing potential (31,32). Second, the increase in risk was seen for SCC specifically.…”