Identification of human liver cytochrome P450 enzymes that metabolize the nonsedating antihistamine loratadine

Yumibe, Nathan; Huie, Keith; Chen, Kwang-Jong; Snow, Mark E.; Clement, Robert P.; Cayen, Mitchell N.

doi:10.1016/0006-2952(95)02169-8

Cited by 95 publications

(73 citation statements)

References 16 publications

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“…Transformation of LOR into DCL is catalyzed by the action of two isoforms of the cytochrome P450, CYP2D6 and CYP3A4. As demonstrated in a previous study, most of the metabolic transformation should be associated with the CYP3A4 activity, but the transformation rate induced by CYP2D6 is five times greater (Yumibe et al, 1996). Reported pharmacokinetic parameters for LOR and DCL obtained after the administration of 20 mg of LOR to Caucasian volunteers have shown a significant variability (Hilbert et al, 1987;Sutherland et al, 2001).…”

Section: Introductionmentioning

confidence: 71%

Validated ion pair liquid chromatography/fluorescence detection method for assessing the variability of the loratadine metabolism occurring in bioequivalence studies

Sora¹,

Udrescu²,

David

et al. 2007

Biomedical Chromatography

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Inter-and intra-individual variability of the loratadine (LOR) metabolism in Caucasian subjects was assessed during a bioequivalence study for two pharmaceutical formulations (solid oral dosage forms) containing 10 mg of the active substance. The analytical data were obtained by applying a reliable, low-cost and sensitive ion pair liquid chromatography/ fluorescence (IPLC/FLD) method for determination of both loratadine and descarboethoxyloratadine (DCL) in human plasma samples. The sample preparation procedure is based on liquid-liquid extraction of the target analytes from alkalinized plasma using diethyl-ether. The separation of the analytes and 8-chloroazatadine as internal standard (IS) was achieved through an isocratic ion pair (IP) elution on a Purospher ® STAR RP-18 column. The mobile phase containing sodium dodecyl sulfate (SDS) as ion pairing agent was pumped at a flow rate of 1 mL/min. Fluorescence detection (FLD) was achieved at 280 nm (excitation) and 440 nm (emission) wavelengths. The increased sensitivity of the method is also based on a large sample injected volume (250 µL). Linear response was found over the 0.5-20 ng/mL concentration interval for both target compounds. Low limits of quantification (LLOQ) around 0.3 ng/mL were found for LOR and DCL. Method validation is presented.

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Section: Introductionmentioning

confidence: 71%

Validated ion pair liquid chromatography/fluorescence detection method for assessing the variability of the loratadine metabolism occurring in bioequivalence studies

Sora¹,

Udrescu²,

David

et al. 2007

Biomedical Chromatography

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“…Loratadine is metabolized to desloratadine by CYP3A4 and CYP2D6 (Yumibe et al, 1996). Takagi et al (2016) demonstrated that CYP-dependent metabolic activation was the key factor in PLD induction of loratadine.…”

Section: Discussionmentioning

confidence: 99%

A cell-based assay using HepaRG cells for predicting drug-induced phospholipidosis

2017

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-The utility of HepaRG cells as an in vitro cell-based assay system for predicting druginduced phospholipidosis (PLD) was investigated. In experiment 1, 10 PLD-positive compounds and 11 PLD-negative compounds were selected. HepaRG cells were treated with each compound for 48 hr. In experiment 2, loratadine and desloratadine, a major metabolite of loratadine, were used to assess metabolic activation for PLD. HepaRG cells were treated with loratadine and desloratadine in the presence or absence of 500 μM 1-aminobenzotriazole (ABT), a broad CYP inhibitor, for 48 hr. After treatment with compounds in experiments 1 and 2, the relative fluorescence intensity (RFI) was measured using LYSO-ID Red dye to assess the PLD induction. In experiment 1, our cell-based assay system using HepaRG cells exhibited 100% sensitivity and 100% specificity for predicting drug-induced PLD. In experiment 2, loratadine increased the RFI in the PLD assay. However, the increase in the RFI was not observed in co-treatment with loratadine and ABT. In addition, desloratadine increased the RFI in the presence and absence of ABT. These results suggested that metabolic activation of loratadine may contribute to PLD in HepaRG cells. We newly demonstrated that HepaRG cells have a high ability for predicting drug-induced PLD. In addition, we newly showed that HepaRG cells may predict drug-induced PLD mediated by metabolic activation of loratadine. Thus, a cell-based assay system using HepaRG cells is a useful model for predicting drug-induced PLD.

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“…These results indirectly prove the occurrence of oxidative stress, but the reactive species that were formed, were scavenged by GSH. Loratadine is processed in liver, and Yumibe et al [28] established through their experiment performed on human liver microsomes that at the first passage through this organ, loratadine is almost complete metabolized by cytochrome P450 to several substances, and one of these is desloratadine. CYP3A4 and CYPP2D6 are the enzymes of the cytochrome P450 that mediate the metabolism of loratadine till the important active metabolite: decarboethoxyloratadine [29].…”

Section: Livermentioning

confidence: 99%

Resveratrol and Loratadine Effects on Oxidative Stress Induced by Experimental Inflammation

Mitrea¹,

Clichici²,

Filip³

et al. 2017

Studia UBB Chemia

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ABSTRACT.Resveratrol is a polyphenol with important antioxidant and antiinflammatory roles. Loratadine, as a selective inverse-agonist of peripheral receptor H1, is described as an anti-allergic substance with potential antiinflammatory effects. We aimed to assess the protective capacity of loratadine against oxidative stress produced by inflammation with carrageenan in comparison with a well-known antioxidant compound, resveratrol.Our results showed that resveratrol and loratadine had no protective anti-inflammatory effects in inflamed skin. As expected, resveratrol had antioxidant effects in serum and in liver. Loratadine developed oxidative stress in tegument and serum.In this experimental model, our results do not sustain the initial hypothesis that loratadine could have a protective effect in inflammation, and, in the contrary, is capable of increasing it, by producing an oxidative stress.

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Identification of human liver cytochrome P450 enzymes that metabolize the nonsedating antihistamine loratadine

Cited by 95 publications

References 16 publications

Validated ion pair liquid chromatography/fluorescence detection method for assessing the variability of the loratadine metabolism occurring in bioequivalence studies

Validated ion pair liquid chromatography/fluorescence detection method for assessing the variability of the loratadine metabolism occurring in bioequivalence studies

A cell-based assay using HepaRG cells for predicting drug-induced phospholipidosis

Resveratrol and Loratadine Effects on Oxidative Stress Induced by Experimental Inflammation

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