Retinal toxicity of chloroquine hydrochloride administered by intraperitoneal injection.
Chloroquine is quinolone derivative known to exert dose-related retinal toxicity, albeit in a variable manner. It is thought that variability in the presentation of chloroquine retinopathy may be the result of perturbations in drug bioavailability subsequent to oral ingestion. In order to better understand the ramifications of bioavailability on the development of retinal injury subsequent to chloroquine use, this study investigated the relationship between retinal injury and chloroquine administration via intraperitoneal rather than oral administration. Four-week-old C57/6J mice underwent daily intraperitoneal injection of 10 mg kg(-1) chloroquine hydrochloride for a total of 62 days. Following treatment, tissue was fixed in preparation for analysis by light and transmission electron microscopy. Treated animals demonstrated marked abnormality of the outer retinal layers described as complete loss of the outer plexiform layer as well as photoreceptors and photoreceptor nuclei. The retinal pigmented epithelium demonstrated focal atrophy, loss of nuclei and pigment irregularity. Findings in the inner retina were notable for the loss of Müller cells and the presence of membranous cytoplasmic bodies. Retinae of control animals were entirely normal. In contrast to previous studies in the murine model examining chloroquine retinopathy subsequent to oral administration, this study suggests that intraperitoneal chloroquine administration facilitates retinal toxicity, presumably due to heightened drug absorption and bioavailability. It is posited that an increased rate of drug accumulation within the retina leads to an enhanced lysosomotrophic drug effect due to inability of the lysosome to compensate for chloroquine-induced elevation in pH through re-acidification of the intra-lysosomal content.
Gaynes
Bruce Ira
BI
Rush University Medical Center, Ophthalmology and Pharmacology, 1725 W. Harrison, Suite 931, Chicago, IL 60612, USA. bgaynes@rush.edu
Torczynski
Elise
E
Varro
Zoltan
Z
Grostern
Richard
R
Perlman
Jay
J
D000818:Animals; D000962:Antimalarials / Q000633:toxicity*; D002738:Chloroquine / Q000633:toxicity*; D002829:Choroid / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D007274:Injections, Intraperitoneal; D051379:Mice; D009900:Optic Nerve / Q000187:drug effects / Q000473:pathology; D010857:Pigment Epithelium of Eye / Q000187:drug effects / Q000648:ultrastructure; D012160:Retina / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D012164:Retinal Diseases / Q000139:chemically induced* / Q000473:pathology
D000962:Antimalarials; D002738:Chloroquine