Paracetamol has been one of the most commonly used and prescribed analgesic drugs for more than a hundred years. Despite being generally well tolerated, it can result in high liver toxicity when administered in specific conditions, such as overdose, or in vulnerable individuals. We have synthesized and characterized a paracetamol galactosylated prodrug (PARgal) with the aim of improving both the pharmacodynamic and pharmacological profile of paracetamol. PARgal shows a range of physicochemical properties, solubility, lipophilicity, and chemical stability at differing physiological pH values and in human serum. PARgal could still be preclinically detected 2 h after administration, meaning that it displays reduced hepatic metabolism compared to paracetamol. In overdose conditions, PARgal has not shown any cytotoxic effect in in vitro analyses performed on human liver cells. Furthermore, when tested in an animal pain model, PARgal demonstrated a sustained analgesic effect up to the 12th hour after oral administration. These findings support the use of galactose as a suitable carrier in the development of prodrugs for analgesic treatment.

Paracetamol-Galactose Conjugate: A Novel Prodrug for an Old Analgesic Drug / Sodano, F.; Lazzarato, L.; Rolando, B.; Spyrakis, F.; De Caro, C.; Magliocca, S.; Marabello, D.; Chegaev, K.; Gazzano, E.; Riganti, C.; Calignano, A.; Russo, Roberto; Rimoli, M. G.. - In: MOLECULAR PHARMACEUTICS. - ISSN 1543-8384. - 16:10(2019), pp. 4181-4189. [10.1021/acs.molpharmaceut.9b00508]

Paracetamol-Galactose Conjugate: A Novel Prodrug for an Old Analgesic Drug

Sodano F.;De Caro C.;Calignano A.;Russo Roberto;Rimoli M. G.
2019

Abstract

Paracetamol has been one of the most commonly used and prescribed analgesic drugs for more than a hundred years. Despite being generally well tolerated, it can result in high liver toxicity when administered in specific conditions, such as overdose, or in vulnerable individuals. We have synthesized and characterized a paracetamol galactosylated prodrug (PARgal) with the aim of improving both the pharmacodynamic and pharmacological profile of paracetamol. PARgal shows a range of physicochemical properties, solubility, lipophilicity, and chemical stability at differing physiological pH values and in human serum. PARgal could still be preclinically detected 2 h after administration, meaning that it displays reduced hepatic metabolism compared to paracetamol. In overdose conditions, PARgal has not shown any cytotoxic effect in in vitro analyses performed on human liver cells. Furthermore, when tested in an animal pain model, PARgal demonstrated a sustained analgesic effect up to the 12th hour after oral administration. These findings support the use of galactose as a suitable carrier in the development of prodrugs for analgesic treatment.
2019
Paracetamol-Galactose Conjugate: A Novel Prodrug for an Old Analgesic Drug / Sodano, F.; Lazzarato, L.; Rolando, B.; Spyrakis, F.; De Caro, C.; Magliocca, S.; Marabello, D.; Chegaev, K.; Gazzano, E.; Riganti, C.; Calignano, A.; Russo, Roberto; Rimoli, M. G.. - In: MOLECULAR PHARMACEUTICS. - ISSN 1543-8384. - 16:10(2019), pp. 4181-4189. [10.1021/acs.molpharmaceut.9b00508]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/772245
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