Journal of Photochemistry and Photobiology A: Chemistry 154 (2003) 245–257 Photophysical and photochemical properties of amitriptyline and nortriptyline hydrochloride: a 266 nm nanosecond laser flash and theoretical study Rafael Arce a,∗ , Carmelo Garc´ ıa b,1 , Rolando Oyola a , Luis Piñero b , Ileana Nieves b , Nadya Cruz b a Department of Chemistry, University of Puerto Rico, R´ ıo Piedras Campus, P.O. Box 23346, San Juan 00931-3346, Puerto Rico b Department of Chemistry, University of Puerto Rico, Humacao Campus, Humacao 00791-4300, Puerto Rico Received 19 July 2002; received in revised form 19 September 2002; accepted 19 September 2002 Abstract Amitriptyline (AMI) and nortriptyline (NT) hydrochlorides were studied by 266 nm laser transient absorption spectroscopy and quantum theoretical calculations. Both drugs photoionize through a biphotonic mechanism producing a radical cation and the solvated electron. A triplet excited state in a twisted conformation around the exocyclic bond is proposed as the intermediate state in the photoionization process. The solvated electron reacts with the ground state drug molecules with rate constants of 6.5 and 5.5 × 10 9 M -1 s -1 to form electron adducts, that absorb in the same wavelength region as the radical cation. Photosensitization experiments using thioxanthone triplet state as the sensitizer demonstrated that AMI or NT quenches this state by a mechanism that depends on the protonation of the amino group in the alkylamine side chain. The protonated species favors energy transfer, while the unprotonated species produces the tricyclic antidepressive radical cation of these drugs and the thioxanthone ketyl radical. These results follow the Rehm–Weller equation for an electron transfer mechanism. Quantum theoretical calculations indicate that ground and excited singlet states photophysical properties of these molecules are determined by the 1,2-diphenylethane system with little participation of the exocyclic double bond. The presence of these primary radicals could explain the reported Type I photodamaging effects for these drugs. © 2003 Elsevier Science B.V. All rights reserved. Keywords: Amitriptyline; Nortriptyline; Laser flash photolysis; Tricyclic antidepressive; Photochemistry and quantum theoretical calculations 1. Introduction Amitriptyline (AMI) and nortriptyline (NT) (Fig. 1) are tricyclics antidepressant drugs (TCA) with a dibenzocyclo- heptene fused ring widely used in mental health care [1–3]. They lack the sulfur and nitrogen atoms found in the pro- mazine derivatives. A “surfactant-like” behavior is conferred by the presence of the alkyl amine side chain. Model studies for the interaction of several TCA with dodecyldimethylam- Abbreviations: AMI, amitriptyline-free base; AMI-HCl, amitriptyline hydrochloride; DPE, 1,1-diphenylethylene; 1,2-DPE, 1,2-diphenylethane; NT, nortriptyline-free base; NT-HCl, nortriptyline hydrochloride; PBS 7.4, pH = 7.4 phosphate buffer saline; PTL-HCl, protriptyline hydrochlo- ride; PTL, protriptyline-free base; TBAP, ter-butyl ammonium perchlo- rate; TCA, tricyclic antidepressants; TX, thioxanthone ∗ Corresponding author. Tel.: +787-764-0000x2433; fax: +787-759-6885. E-mail addresses: rarce@goliath.cnnet.clu.edu (R. Arce), c garcia@cuhac.upr.clu.edu (C. Garc´ ıa). 1 Co-corresponding author. Tel.: +787-850-9387; fax: +787-850-9422. monium chloride [4] and sodium dodecyl sulfate micelles [5] have shown that AMI adopts an extended conforma- tion in the micelle. The N-methyl propylamine side chain resides close to the micelle surface and the tricyclic group penetrates the hydrophobic region. These results indicate that the interaction of TCAs with biological membranes is fundamental in their biological activity. A demethylation process converts AMI into NT, one of its main metabolic products [6,7]. Since both molecules have similar molecu- lar structures, their chemical properties are not expected to differ much. As a matter of fact, patients treated with these TCAs show similar side effects when exposed to sunlight, although to different extent when compared to other related TCAs [8,9]. The major side effect induced by these two TCAs is a skin slate-gray discoloration, which can last for years after cessation of therapy [10]. Recently, Dall’Acqua et al. [11] reported that AMI pho- totoxicity can promote cell death even at a concentration of 100 M and UVA doses in the range of 3.3–6.6 J cm -2 . A negligible production of singlet oxygen (Type II photo- 1010-6030/03/$ – see front matter © 2003 Elsevier Science B.V. All rights reserved. PII:S1010-6030(02)00353-2