The Stepwise Biphotonic Photoionization of Chlorpromazine as Seen by Laser Flash Photolysis

Abstract

It is generally accepted that both promazine (PZ) and chlorpromazine (CPZ) photionize monophotonically to their respective cation radicals and the corresponding hydrated electrons. It is also supposed that this photoinization has a role in the phototoxic effects of these drugs. However, using laser flash photolysis, we have observed that photoionization of CPZ during S1 excitation (lambda greater than 300 nm) is a stepwise biphotonic process. In the case of PZ our flash photolysis results are less clearcut, but are consistent with stepwise biphotonic photoionization for S1 excitation. We demonstrate, using computer simulation of the intramolecular kinetics, that the estimated triplet state lifetime of CPZ is sufficiently long (23 ns at room temperature) to account for the apparent monophotonic photoionization that has been observed by others at high light intensities and short pulse times. Our laser flash photolysis results also suggest that the photo-ionization mechanism of PZ and CPZ is wavelength-dependent. Both drugs exhibit apparent monophotonic photoionization when they are excited at 266 nm under conditions of laser pulse width and intensity similar to those at 355 nm. We suggest that photoionization is not an important mechanism in the observed phototoxic and photoallergic effects of PZ and CPZ in sunlight.

Exposure of Chlorpromazine to 266 nm Laser Beam Generates New Species with Antibacterial Properties: Contributions to Development of a New Process for Drug Discovery

“…Interestingly, this product emits fluorescence and is not seen with exposures of higher concentrations of CPZ, nor is it observed with prolonged exposures of concentrations higher than 2 mg/mL. We interpret these findings to suggest that the rapid formation of products from CPZ at its lowest concentration yields a radical that is short lived and slightly more polar than CPZ and that it may represent a species that contains the sulfoxide previously suggested from flash photolysis of CPZ [32]. Monitoring the pH of the 2 mg/mL of CPZ during exposure indicated a rapid drop of 3 to 4 pH units within 5 minutes that was maintained for the duration of the two hour exposure (data not shown).…”

“…These studies showed that white light [28], incoherent UV light [31], coherent UV [48] and “flash photolysis” by a 266 nm laser [32], produced changes in structure of CPZ. The changes were perceived from indirect measurements that suggested the formation of radicals leading to the substitution at the sulfur atom (sulfoxides) and loss of the chloride at C-2 forming PZ.…”

“…These changes were also perceived as “destruction” of the CPZ molecule, and the use of light to bring about this “destruction” was termed “photolysis” [27], [34], [35], [49]. Nevertheless, because the energy of a laser beam is thousands of times greater than that generated by UV light sources, we considered the possibility that lasers could be used to rapidly modify molecules with prolongation of exposure to hours rather than nanoseconds [32] and perhaps be used to produce reactions not possible with routine pyrogenic techniques used in organic chemistry. The CPZ is the second most studied compound next to aspirin (search in PubMed yielded 20,000 articles on CPZ versus 49,000 for aspirin).…”

“…Consequently, the effect of light on CPZ has been studied extensively. The effect of laser beams on the structure of CPZ has been previously studied [32], [33]. These studies suggested that using laser flash photolysis, the photoionization of CPZ during S 1 excitation (wavelength greater than 300 nm) is a stepwise biphotonic process.…”

Photosensitization of Biomolecules by Phenothiazine Derivatives

“…Thus phenothiazines photoionization has been clearly demonstrated by several groups using transient absorption spectroscopy or EPR, but controversy remains over the mechanism of photoionization of these compounds. Motten et al [33], Buetner et al [34] and Hall et al [35] in contrast to the previous works proposed a wavelength-dependent photoionization of CPZ and promazine (PMZ) involving stepwise biphotonic photoionization through the triplet state at wavelength> 280 nm and monophotonic photoionization at wavelength <300 nm: this wavelength dependence suggest that the mechanism for cutaneous phototoxicity associated with clinical use of CPZ, which occur at solar wavelength >300 nm does not involve photoionization. More recently Garcia et al [36] in an elegant study using conditions where absorption by singlet or triplet excited states occur selectively have confirmed that photoionization occurs through biphotonic excitation for CPZ and PZ.…”