Advances in high-resolution MS and hepatocyte models solve a long-standing metabolism challenge: the loratadine story.

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Aratyn-Schaus Y, Ramanathan R

Advances in high-resolution MS and hepatocyte models solve a long-standing metabolism challenge: the loratadine story.

Bioanalysis. 2016 Aug;8(16):1645-62. doi: 10.4155/bio-2016-0094. Epub 2016 Jul 27.

PubMed ID

27460981 [ View in PubMed

]

Abstract

BACKGROUND: Loratadine (LOR, Claritin((R))) is a long-acting antihistamine used to treat allergic rhinitis. The major active human metabolite, desloratadine (DL, Clarinex((R))), is extensively metabolized to 3-hydroxydesloratadine (3-OH-DL) (M40) and subsequently glucuronidated before elimination. This study revealed the ability of a novel, long-term hepatocyte micropatterned co-culture (MPCC) model to generate in vivo metabolites. Metabolites were detected and characterized using non-targeted MS/MS(ALL) with SWATH acquisition by a UHPLC-Q-TOF system. Results & methodology: Human MPCCs extensively metabolized LOR and formed 3-OH-DL-glucuronide (M13). Cross-species comparisons revealed monkey- and rat-specific metabolites with gender-specific DL-pyridine-N-oxide formation in male rats. These results demonstrate a first for an in vitro hepatocyte model to generate circulating metabolites of LOR and detect species-specific differences. Early focus on human metabolites could have spared characterization of nonhuman metabolites in preclinical species.

DrugBank Data that Cites this Article

Drugs

Loratadine

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Loratadine	Cytochrome P450 1A1	Protein	Humans	No	Substrate	Details
Loratadine	Cytochrome P450 2C19	Protein	Humans	No	Substrate Inhibitor	Details
Loratadine	UDP-glucuronosyltransferase 1-1	Protein	Humans	Unknown	Not Available	Details
Loratadine	UDP-glucuronosyltransferase 1-3	Protein	Humans	Unknown	Not Available	Details
Loratadine	UDP-glucuronosyltransferase 2B15	Protein	Humans	Unknown	Not Available	Details

Drug Reactions

Reaction
Loratadine DB00455 Cytochrome P450 3A4 Cytochrome P450 2D6 Cytochrome P450 2C19 Cytochrome P450 1A1 Descarboethoxyloratadine DBMET00377	Details
Loratadine DB00455 Cytochrome P450 1A1 Cytochrome P450 2B6 Cytochrome P450 2C8 Cytochrome P450 2C9 Cytochrome P450 2C19 Cytochrome P450 2D6 Cytochrome P450 3A4 Cytochrome P450 3A5 hydroxylated metabolite, loratadine DBMET02790	Details