Gender differences in limonin pharmacokinetics in rats

Liang, Yan; Xie, Lin; Liu, X. D.; Hu, Yunwei; Tong, L.; Wang, G. J.

doi:10.1007/bf03190627

Cited by 7 publications

(3 citation statements)

References 7 publications

(9 reference statements)

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“…Gender-related pharmacokinetic differences of orally dosed warfarin, a coumarin anticoagulant, in rats were observed by Zhu and Shin [7], which showed a significant greater exposure of warfarin in females than males. It was also found by Liang et al that the plasma concentrations of limonin in female rats were significantly higher (p<0.01) than those in male rats as assessed by 50-fold and 3-fold higher AUC in female rats than those in male rats after oral (36 mg/kg) and intravenous (3.6 mg/kg) administration of limonin, respectively [8]. Yang et al reported that the AUC of ondansetron, a potent and selective 5-HT 3 receptor antagonist, in male rats were significantly smaller, 22.6% and 58.8%, than those in female rats after intravenous and oral administration of the drug, respectively [9].…”

Section: Introductionsupporting

confidence: 66%

Gender Specific Drug Metabolism of PF-02341066 in Rats — Role of Sulfoconjugation

Zhong

Zhan²,

Kang³

et al. 2010

CDM

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PF-02341066 is a selective c-Met/Alk tyrosine kinase inhibitor currently in clinical development as an anticancer agent. Non-clinical toxicokinetic evaluation in rats revealed gender-related differences in pharmacokinetics with at least 2-fold higher PF-02341066 plasma concentrations in males than females when administered the same dose. In general, lower systemic exposure of drugs that undergoes oxidative metabolism in male than female rats has been well known to be attributed to gender-specific expression of CYP genes in rats. It is of interest to understand why the gender-related pharmacokinetics in rats for PF-02341066 was opposite to the general observations and if the gender-related pharmacokinetics would be seen in humans that may impact the drug efficacy and toxicity profiles. The potential gender-related differences in PF-02341066 metabolism were investigated both in vitro and in vivo using [(3)H]PF-02341066. Oxidation was found to be the major metabolic pathway in male rat liver S9 incubations whereas sulfoconjugation was the predominant metabolic pathway in females. There was no qualitative difference in metabolite profiles of PF-02341066 between man and woman liver S9 incubations. Following a single oral administration of [(3)H]PF-02341066 to rats at 150 mg/kg, the primary route of excretion of the radioactivity was via feces, in which, the most abundant radio-component in male rat was the parent drug (29% of dose) and in female rat was the parent sulfate (44% of dose). The more extensive formation of the parent sulfoconjugate in female rats most likely explains why the female rat had lower drug exposure compared to male rat, as gender-related changes of sulfotransferase expression were widely reported in rats. The human liver S9 study suggests that gender-related pharmacokinetics of PF-02341066 are unlikely to occur in humans.

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Section: Introductionsupporting

confidence: 66%

Gender Specific Drug Metabolism of PF-02341066 in Rats — Role of Sulfoconjugation

Zhong

Zhan²,

Kang³

et al. 2010

CDM

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“…Similarly, the PK profile of limonin in rats demonstrated the existence of marked gender differences. The exposures of the female rats were 50-fold higher than those in the male rats after oral administration, and three-fold higher after intravenous administration [ 27 ]. Furthermore, the AUC was not directly proportional to the dosage, and HY-071085 showed significant nonlinear kinetic characteristics in rats.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Drug Pharmacokinetic, Tissue Distribution and Excretion Profiles of the Novel Limonin Derivate HY-071085 as an Anti-Inflammatory and Analgesic Candidate in Rats and Beagle Dogs

et al. 2022

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Limonin is one of the research hotspots in natural drug development. However, its low solubility in water leads to poor oral bioavailability, discouraging the further study of its potential as a candidate compound. In order to overcome this limitation, and to enhance its biological activities, a novel limonin derivative—HY-071085—was synthesized by structural modification, and has exhibited strong anti-inflammatory and analgesic activity. In order to achieve a thorough understanding of the biological actions of HY-071085 in vivo, this study evaluated the pharmacokinetics and bioavailability of HY-071085 in rats and beagle dogs, and the distribution and excretion in rats. Using ultra-high-performance liquid chromatography-tandem mass spectrometry, the kinetic profiles of HY-071085 in the plasma of healthy rats and beagle dogs after a single gavage, repeated gavages and the intravenous injection of HY-071085 were studied. The tissue distribution (heart, liver, spleen, lung, kidney, gastric tissue, intestine, brain, skin, testis, ovary and womb) and excretion of HY-071085 were also studied. These results showed that HY-071085 has nonlinear dynamic characteristics in rat and beagle dog plasma. It was found that the plasma concentrations of HY-071085 in female rats were significantly higher than those in male rats after a single oral administration. There were gender differences in the kinetic behavior of HY-071085 in rats; however, there was no difference identified in dogs. HY-071085 was mainly eliminated as metabolites in rats, and was distributed in most of the tissues except the brain, with the highest content being in the gastric tissue and intestinal arease, followed by the liver, spleen, fat, lung, kidney, ovary and heart. The bioavailability of HY-071085 in male and female rats was 2.8% and 10.8%, respectively, and was about 13.1% in beagle dogs. The plasma protein binding rate of HY-071085 in rats, beagle dogs and humans ranged from 32.9% to 100%, with obvious species differences. In conclusion, our study provides useful information regarding the absorption, distribution and excretion of HY-071085, which will provide a good base for the study of the mechanism of its biological effects.

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“…The C max and AUC of limonin in female rats were found to be much higher than those in males. Further studies revealed that the gender differences of CYP3A2 and CYP2C11 in liver microsomes of rats might be the main reason for gender differences in pharmacokinetics [132,133]. Furthermore, we also summarized the relevant pharmacokinetic parameters of limonin in animals in Table 4, in order to provide reference for the preclinical pharmacokinetic study of limonin.…”

Section: Pharmacokineticsmentioning

confidence: 99%

Limonin: A Review of Its Pharmacology, Toxicity, and Pharmacokinetics

et al. 2019

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Limonin is a natural tetracyclic triterpenoid compound, which widely exists in Euodia rutaecarpa (Juss.) Benth., Phellodendron chinense Schneid., and Coptis chinensis Franch. Its extensive pharmacological effects have attracted considerable attention in recent years. However, there is no systematic review focusing on the pharmacology, toxicity, and pharmacokinetics of limonin. Therefore, this review aimed to provide the latest information on the pharmacology, toxicity, and pharmacokinetics of limonin, exploring the therapeutic potential of this compound and looking for ways to improve efficacy and bioavailability. Limonin has a wide spectrum of pharmacological effects, including anti-cancer, anti-inflammatory and analgesic, anti-bacterial and anti-virus, anti-oxidation, liver protection properties. However, limonin has also been shown to lead to hepatotoxicity, renal toxicity, and genetic damage. Moreover, limonin also has complex impacts on hepatic metabolic enzyme. Pharmacokinetic studies have demonstrated that limonin has poor bioavailability, and the reduction, hydrolysis, and methylation are the main metabolic pathways of limonin. We also found that the position and group of the substituents of limonin are key in affecting pharmacological activity and bioavailability. However, some issues still exist, such as the mechanism of antioxidant activity of limonin not being clear. In addition, there are few studies on the toxicity mechanism of limonin, and the effects of limonin concentration on pharmacological effects and toxicity are not clear, and no researchers have reported any ways in which to reduce the toxicity of limonin. Therefore, future research directions include the mechanism of antioxidant activity of limonin, how the concentration of limonin affects pharmacological effects and toxicity, finding ways to reduce the toxicity of limonin, and structural modification of limonin—one of the key methods necessary to enhance pharmacological activity and bioavailability.

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Gender differences in limonin pharmacokinetics in rats

Cited by 7 publications

References 7 publications

Gender Specific Drug Metabolism of PF-02341066 in Rats — Role of Sulfoconjugation

Gender Specific Drug Metabolism of PF-02341066 in Rats — Role of Sulfoconjugation

Preclinical Drug Pharmacokinetic, Tissue Distribution and Excretion Profiles of the Novel Limonin Derivate HY-071085 as an Anti-Inflammatory and Analgesic Candidate in Rats and Beagle Dogs

Limonin: A Review of Its Pharmacology, Toxicity, and Pharmacokinetics

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Gender differences in limonin pharmacokinetics in rats

Cited by 7 publications

References 7 publications

Gender Specific Drug Metabolism of PF-02341066 in Rats &#x2014; Role of Sulfoconjugation

Gender Specific Drug Metabolism of PF-02341066 in Rats &#x2014; Role of Sulfoconjugation

Preclinical Drug Pharmacokinetic, Tissue Distribution and Excretion Profiles of the Novel Limonin Derivate HY-071085 as an Anti-Inflammatory and Analgesic Candidate in Rats and Beagle Dogs

Limonin: A Review of Its Pharmacology, Toxicity, and Pharmacokinetics

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Gender Specific Drug Metabolism of PF-02341066 in Rats — Role of Sulfoconjugation

Gender Specific Drug Metabolism of PF-02341066 in Rats — Role of Sulfoconjugation