UV-photodegradation of desipramine: Impact of concentration, pH and temperature on formation of products including their biodegradability and toxicity.

Desipramine (DMI) is a widely used tricyclic antidepressant, and it is the major metabolite of imipramine (IMI) and lofepramine (LMI); IMI and LMI are two of the most commonly used tricyclic antidepressants. If DMI enters the aquatic environment, it can be transformed by the environmental bacteria or UV radiation. Therefore, photolysis of DMI in water was performed using a simulated sunlight Xenon-lamp and a UV-lamp. Subsequently, the biodegradability of DMI and its photo-transformation products (PTPs) formed during its UV photolysis was studied. The influence of variable conditions, such as initial DMI concentration, solution pH, and temperature, on DMI UV photolysis behavior was also studied. The degree of mineralization of DMI and its PTPs was monitored. A Shimadzu HPLC-UV apparatus was used to follow the kinetic profile of DMI during UV-irradiation; after that, ion-trap and high-resolution mass spectrometry coupled with chromatography were used to monitor and identify the possible PTPs. The environmentally relevant properties and selected toxicity properties of DMI and the non-biodegradable PTPs were predicted using different QSAR models. DMI underwent UV photolysis with first-order kinetics. Quantum yields were very low. DOC values indicated that DMI formed new PTPs and was not completely mineralized. Analysis by means of high-resolution mass spectrometry revealed that the photolysis of DMI followed three main photolysis pathways: isomerization, hydroxylation, and ring opening. The photolysis rate was inversely proportional to initial DMI concentration. The pH showed a significant impact on the photolysis rate of DMI, and on the PTPs in terms of both formation kinetics and mechanisms. Although temperature was expected to increase the photolysis rate, it showed a non-significant impact in this study. Results from biodegradation tests and QSAR analysis revealed that DMI and its PTPs are not readily biodegradable and that some PTPs may be human and/or eco-toxic, so they may pose a risk to the environment.

The photochemical stability of cis- and trans-isomers of tricyclic neuroleptic drugs.

The irradiation of the tranquillizers flupenthixol, clopenthixol and chlorprothixene has been found to induce rapid cis-trans isomerization. The composition of the photosatitionary mixture is not that of the batch drug and hence this process may affect the activity. Further decomposition to a thioxanthone derivative occurs rapidly in the presence of air. Exclusion of oxygen, however, does not prevent further degradation and a slower secondary isomerization is observed on prolonged irradiation. Doxepin and dothiepin also undergo analogous reactions but the isomerizations are much slower and the oxidative degradation yields many products.

Isolation and identification of the photodegradation products of the photosensitizing antidepressant drug clomipramine. Phototoxicity studies on erythrocytes.

The isolation and identification of the photodegradation products of clomipramine (CIP) in phosphate buffered saline (PBS pH 7.4 and 6.0) solution and methanol under aerobic conditions were studied. Six compounds were identified and four of them were isolated and characterized by spectroscopic methods. A radical mechanism with the participation of the solvent is proposed for the photodegradation of CIP which undergoes homolytic cleavage of the carbon-chlorine bond and also photooxidation of the amine group. CIP was able to induce photohemolysis when it was irradiated in PBS pH 7.4 and in PBS pH 6.0 containing a suspension of human red blood cells (RBCs). The photohemolysis experiments in the presence of additives DABCO and GSH showed nearly total inhibition of drug-induced photohemolysis. The efficient inhibition of photohemolysis by the radical scavenger GSH compared with the inhibition show by DABCO suggests a moderate effect by singlet oxygen. Clomipramine-N-oxide was the unique photoproduct able to induce hemolysis and photohemolysis when it was incubated and irradiated with RBCs for 1 h. A mechanism involving singlet oxygen, radicals and photoproducts is suggested for the reported phototoxicity.