Bioequivalence between trademark and generic acetaminophen and their effects over embryonic development using zebrafish (Danio rerio) as model organism

VANESSA P. CEDRON; LAURA SANCHEZ; MANUEL VERA; ANDREA M.J. WEINER; JUAN RUBIOLO

Buenos Aires

Congreso; LASDB Meeting 2019; 2019

LASDB

In spite of its toxic effects (affecting mainly the liver, where the compound is metabolized), N-acetyl-p-aminophenol (APAP), also commonly known as paracetamol, is one of the most widely used analgesic and antipyretic agents (even in pregnant women). It can be obtained without a medical prescription. Due to this use, trademark and generic compounds are available in the market and are expected to be bioequivalent. To test this bioequivalence and the APAP effects over the embryonic development, a Fish Embryo acute Toxicity (FET) test was carried out with the pure APAP compound, a generic drug, and a reference drug using zebrafish embryos. FET results confirmed the bioequivalence among the different APAP compounds used, with similar and non-statistically significant Lethal Concentrations (LC) values, suggesting no toxicity effects of excipients. Diminished pigmentation (in treated 0 h post-fertilization embryos) and blockage of melanin synthesis (in treated 72 h post-fertilization larvae) was detected, suggesting the involvement of this compound in the development of black pigment cells as described recently for human epidermal melanocytes. Morphological abnormalities such as aberrant craniofacial structures, pericardial edemas, and blood accumulation were also found. All these effects could be due to higher levels of apoptotic cells detected in treated embryos. Therefore, teratogenic effects of acetaminophen cannot be ruled out, and its wide use should be revised.