The effects of P-glycoprotein inhibitor zosuquidar on the sex and time-dependent pharmacokinetics of parenterally administered talinolol in mice

Kara, Zeliha Pala; Civelek, Dilek Ozturk; Öztürk, Dilek; Okyar, Alper

doi:10.1016/j.ejps.2020.105589

Cited by 5 publications

(3 citation statements)

References 47 publications

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“…For instance, zosuquidar has commonly been applied to alter the distribution of P-gp substrates to the CNS by inhibition of P-gp mediated cellular efflux in the blood-brain barrier ( Bihorel et al, 2007 ; Chen et al, 2009 ; Choo et al, 2000 ; Dai et al, 2003 ; Karssen et al, 2002 ; Mittapalli et al, 2012 ; Nagaya et al, 2020 ) and to a lesser extent to increase the oral absorption of P-gp substrates ( Adane et al, 2012 ; Al-Ali et al, 2020 ; Bardelmeijer et al, 2004 ; Matsuda et al, 2013 ; Mouly et al, 2004 ; Kono et al, 2021 ; Tsukimoto et al, 2015 ). Recently, the influence of factors such as sex, dosing time, and food intake on P-gp expression and function in the small intestine has also been investigated ( Dou et al, 2020 ; Mai et al, 2019 ; Mai et al, 2018 ; Mai et al, 2021 ), and zosuquidar has been applied as an inhibitor in this context as well ( Kara et al, 2021 ). However, a thorough understanding of zosuquidar doses needed to increase oral absorption of P-gp substrates, as well as information about the pharmacokinetics of zosuquidar itself, are missing, and both are needed to apply zosuquidar in formulation design.…”

Section: Introductionmentioning

confidence: 99%

Oral etoposide and zosuquidar bioavailability in rats: Effect of co-administration and in vitro-in vivo correlation of P-glycoprotein inhibition

Nielsen

Holm

Pijpers

et al. 2021

International Journal of Pharmaceutics: X

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P-glycoprotein inhibitors, like zosuquidar, have widely been used to study the role of P-glycoprotein in oral absorption. Still, systematic studies on the inhibitor dose-response relationship on intestinal drug permeation are lacking. In the present study, we investigated the effect of 0.79 nM-2.5 μM zosuquidar on etoposide permeability across Caco-2 cell monolayers. We also investigated etoposide pharmacokinetics after oral or IV administration to Sprague Dawley rats with co-administration of 0.063–63 mg/kg zosuquidar, as well as the pharmacokinetics of zosuquidar itself. Oral zosuquidar bioavailability was 2.6–4.2%, while oral etoposide bioavailability was 5.5 ± 0.9%, which increased with increasing zosuquidar doses to 35 ± 5%. The intestinal zosuquidar concentration required to induce a half-maximal increase in bioavailability was estimated to 180 μM. In contrast, the IC 50 of zosuquidar on etoposide permeability in vitro was only 5–10 nM, and a substantial in vitro-in vivo discrepancy of at least four orders of magnitude was thereby identified. Overall, the present study provides valuable insights for future formulation development that applies fixed dose combinations of P-glycoprotein inhibitors to increase the absorption of poorly permeable P-glycoprotein substrate drugs.

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Section: Introductionmentioning

confidence: 99%

Oral etoposide and zosuquidar bioavailability in rats: Effect of co-administration and in vitro-in vivo correlation of P-glycoprotein inhibition

Nielsen

Holm

Pijpers

et al. 2021

International Journal of Pharmaceutics: X

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“…Pharmacokinetic parameters of capecitabine and its metabolites were calculated by the non-compartmental pharmacokinetic analysis method using Excel (Microsoft Office, USA) (Ozturk et al, 2017; Pala Kara et al, 2021). Peak plasma concentration ( C max ) and time to reach peak concentration ( t max ) values were directly obtained from the concentration-time curves.…”

Section: Methodsmentioning

confidence: 99%

Diurnal Changes in Capecitabine Clock-Controlled Metabolism Enzymes Are Responsible for Its Pharmacokinetics in Male Mice

et al. 2023

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The circadian timing system controls absorption, distribution, metabolism, and elimination processes of drug pharmacokinetics over a 24-h period. Exposure of target tissues to the active form of the drug and cytotoxicity display variations depending on the chronopharmacokinetics. For anticancer drugs with narrow therapeutic ranges and dose-limiting side effects, it is particularly important to know the temporal changes in pharmacokinetics. A previous study indicated that pharmacokinetic profile of capecitabine was different depending on dosing time in rat. However, it is not known how such difference is attributed with respect to diurnal rhythm. Therefore, in this study, we evaluated capecitabine-metabolizing enzymes in a diurnal rhythm-dependent manner. To this end, C57BL/6J male mice were orally treated with 500 mg/kg capecitabine at ZT1, ZT7, ZT13, or ZT19. We then determined pharmacokinetics of capecitabine and its metabolites, 5′-deoxy-5-fluorocytidine (5′DFCR), 5′-deoxy-5-fluorouridine (5′DFUR), 5-fluorouracil (5-FU), in plasma and liver. Results revealed that plasma Cmax and AUC0-6h (area under the plasma concentration-time curve from 0 to 6 h) values of capecitabine, 5′DFUR, and 5-FU were higher during the rest phase (ZT1 and ZT7) than the activity phase (ZT13 and ZT19) ( p < 0.05). Similarly, Cmax and AUC0-6h values of 5′DFUR and 5-FU in liver were higher during the rest phase than activity phase ( p < 0.05), while there was no significant difference in liver concentrations of capecitabine and 5′DFCR. We determined the level of the enzymes responsible for the conversion of capecitabine and its metabolites at each ZT. Results indicated the levels of carboxylesterase 1 and 2, cytidine deaminase, uridine phosphorylase 2, and dihydropyrimidine dehydrogenase ( p < 0.05) are being rhythmically regulated and, in turn, attributed different pharmacokinetics profiles of capecitabine and its metabolism. This study highlights the importance of capecitabine administration time to increase the efficacy with minimum adverse effects.

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“…Separately, mice were administrated with MLT (1.0 mg/kg, i.g.) and anaesthetized by urethane, and liver tissues were collected at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 h for time-course studies ( n = 4). − Additionally, mice were gavaged with MLT at dosages of 0.1, 0.2, 0.5, 1, 10, and 20 mg/kg. The animals were anaesthetized by urethane, and liver tissues were harvested at pointed time after administration for dosage-dependent experiments ( n = 4).…”

Section: Experimental Proceduresmentioning

confidence: 99%

Metabolic Activation of Militarine In Vitro and In Vivo

Zou

Wang

et al. 2022

Chem. Res. Toxicol.

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Bletilla striata is consumed as food and herbal medicine. Militarine (MLT) is a major ingredient in B. striata. Previous studies demonstrated that MLT showed teratogenic toxicity to zebrafish embryos. The present study aimed to identify reactive metabolites possibly involved in the cytotoxicity of MLT and determine the metabolic pathways involved. MLT was found to be hydrolyzed to p-hydroxybenzyl alcohol (HBA) by β-glucosidase and esterases. The resulting HBA further underwent spontaneous dehydration to form quinone methide. HBA was also metabolized to the corresponding sulfate, followed by departure of the sulfate to generate a quinone methide. The resultant quinone methide reacted with hepatic glutathione (GSH) and protein to form the corresponding GSH conjugate and protein adduction. Additionally, inhibition of sulfotransferases (SULTs) attenuated the susceptibility of hepatocytes to the toxicity of MLT. This study provides that the hydrolytic enzymes β-glucosidase, esterases, and SULTs participate in the metabolic activation of MLT.

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The effects of P-glycoprotein inhibitor zosuquidar on the sex and time-dependent pharmacokinetics of parenterally administered talinolol in mice

Cited by 5 publications

References 47 publications

Oral etoposide and zosuquidar bioavailability in rats: Effect of co-administration and in vitro-in vivo correlation of P-glycoprotein inhibition

Oral etoposide and zosuquidar bioavailability in rats: Effect of co-administration and in vitro-in vivo correlation of P-glycoprotein inhibition

Diurnal Changes in Capecitabine Clock-Controlled Metabolism Enzymes Are Responsible for Its Pharmacokinetics in Male Mice

Metabolic Activation of Militarine In Vitro and In Vivo

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