Effect of CYP3A4 metabolism on sex differences in the pharmacokinetics and pharmacodynamics of zolpidem

Yoon, Seo Young; Jeong, Seongmee; Jung, Eben; Kim, Ki Soon; Jeon, Inseung; Lee, Yujin; Cho, Joo Youn; Oh, Woo Yong; Chung, Jae‐Yong

doi:10.1038/s41598-021-98689-z

Cited by 32 publications

(22 citation statements)

References 33 publications

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“…WT and rTg4510 mice exhibited a relatively similar decrease in wake and increase in NREM sleep/TST following zolpidem administration, with a slightly larger effect size in male mice. REM sleep across the active phase, however, was decreased only in female WT mice, suggesting a sex difference in responses to zolpidem, which may be related to sex differences in metabolism of this drug, as is noted in rats and humans (Peer et al, 2016;Yoon et al, 2021) et al, 2006). This supports the finding of the present study that male mice respond more prominently to hypnotic compounds but does not explain the transient response of female rTg4510 mice to MK-1064, but not zolpidem or suvorexant.…”

Section: Discussionmentioning

confidence: 87%

Differential sleep/wake response and sex differences following acute suvorexant, MK‐1064 and zolpidem administration in the rTg4510 mouse model of tauopathy

Keenan

Daykin

Chu

et al. 2022

British J Pharmacology

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Background and Purpose Transgenic mouse models of tauopathy display prominent sleep/wake disturbances which manifest primarily as a hyperarousal phenotype during the active phase, suggesting that tau pathology contributes to sleep/wake changes. However, no study has yet investigated the effect of sleep‐promoting compounds in these models. Such information has implications for the use of hypnotics as potential therapeutic tools in tauopathy‐related disorders. Experimental Approach This study examined polysomnographic recordings in 6‐6.5‐month‐old male and female rTg4510 mice following acute administration of suvorexant (50 mg·kg−1), MK‐1064 (30 mg·kg−1) or zolpidem (10 mg·kg−1), administered at the commencement of the active phase. Key Results Suvorexant, a dual OX receptor antagonist, promoted REM sleep in rTg4510 mice, without affecting wake or NREM sleep. MK‐1064, a selective OX2 receptor antagonist, reduced wake and increased NREM and total sleep time. MK‐1064 normalised the hyperarousal phenotype of male rTg4510 mice, whereas female rTg4510 mice exhibited a more transient response. Zolpidem, a GABAA receptor positive allosteric modulator, decreased wake and increased NREM sleep in both male and female rTg4510 mice. Of the three compounds, the OX2 receptor antagonist MK‐1064 promoted and normalised physiologically normal sleep, especially in male rTg4510 mice. Conclusions and Implications Our findings indicate that hyperphosphorylated tau accumulation and associated hyperarousal does not significantly alter the responses of tauopathy mouse models to hypnotics. However, the sex differences observed in the sleep/wake response of rTg4510 mice to MK‐1064, but not suvorexant or zolpidem, raise questions about therapeutic implications for the use of OX2 receptor antagonists in human neurodegenerative disorders.

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Section: Discussionmentioning

confidence: 87%

Differential sleep/wake response and sex differences following acute suvorexant, MK‐1064 and zolpidem administration in the rTg4510 mouse model of tauopathy

Keenan

Daykin

Chu

et al. 2022

British J Pharmacology

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“…It is generally believed that women have higher CYP3A4 activity than men, 3,8 but in some drugs of CYP3A4 substrates, such as zolpidem, the Cps are higher in women. 9 The limitations of our study were the small number of study patients, and the comparison of racial differences was not performed by a well-controlled head-to-head design. In conclusion, we suggest that the therapeutic range of lurasidone be 10 to 15 ng/mL, and compared with Western patients, ethnic Chinese or East Asian patients might have a 30% to 40% higher steady-state Cps under the same dose.…”

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confidence: 95%

“…8 Recently, SNSs are being used not just for exchanging messages with peers but also for posting photos to show that their real life is fulfilling, reporting to others that they are happier than they are, or are experiencing self-satisfying gratification by receiving a lot of 'like' clicks for their comments or photos. 9 In other words, SNSs have become a tool to compensate for their feelings that cannot be satisfied in their real lives. Smartphone users with a sense of loneliness may spend a lot of time on SNSs to relieve their psychological pain by pretending to be someone who is living a full life.…”

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confidence: 99%

Therapeutic Drug Monitoring of Lurasidone in Patients with Schizophrenia or Bipolar Disorder: A preliminary study

Huang

Lin

2022

Psychiatry Clin Neurosci

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Lurasidone is a second-generation antipsychotic agent indicated for schizophrenia and bipolar depression. Lurasidone is metabolized mainly by cytochrome P450 (CYP) 3A4, and drug-drug interaction needs to be considered. 1 Plasma concentrations (Cps) in 44 clinically stable patients (mean age, 47.8 AE 12.9 years, body weight [BW] 71.4 AE 14.8 kg) taking lurasidone for at least 1 month with informed consent were monitored after dosing for around 15 hours. Table 1 presents the mean Cps, Cps/daily dose (DD), and Cps/DD/BW among the patients and the breakdown by sex. Pearson correlation coefficient for Cps and DD/BW was 0.036, suggesting a wide interindividual range. Many factors contribute to this variation, such as genetic differences in the first-pass effect of the CYP system, sex, medication adherence, dosing time, and whether the medication is taken with meals. Because CYP3A4 plays a major role in the metabolism of lurasidone, this system exhibits remarkable interindividual activity variation as high as 20-fold 2 and racial genetic differences. 3 These differences may account for some of the Cps variations in the results.As most patients were in stable clinical condition, we assumed that their prescribed lurasidone dosage was suitable. Considering that the elimination half-life of lurasidone is approximately 18 hours, 4 and that our results were from approximately 15 hours after dosing, the trough mean Cps should be adjusted by 85% to 13.0 ng/mL and the median to 10.9 ng/mL. Using our preliminary results, we suggest that the therapeutic range of lurasidone in the maintenance phase be 10 to 15 ng/mL, which is slightly lower than the suggested range of 15 to 40 ng/mL by Hiemke et al. 5 In a study of 38 healthy Chinese men administered a 40-mg dose of lurasidone, 6 the area under the curve was 37% higher in Chinese than in Western participants. Findling et al. 7 conducted a pharmacokinetic study of lurasidone in children and adolescents and found it was similar to exposure observed at a steady state in adults. In the group receiving 80 mg/day, the 15 h Cps was approximately 9.5 ng/mL by extrapolation, which is approximately 40% lower than our results (15.7 AE 12.8 ng/mL, n = 35). From these two independent results, we infer that Chinese individuals might have a 30% to 40% higher Abbreviations: BW, body weight; Cps, plasma concentrations; DD, daily dose.

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“…Another reason could be the gender-specific difference in CYP3A activity. Endogenous sex hormones reportedly affect CYP3A activity (Yoon et al, 2021). Ticagrelor is also a P-glycoprotein substrate.…”

Section: Discussionmentioning

confidence: 99%

Effect of CYP4F2 Polymorphisms on Ticagrelor Pharmacokinetics in Healthy Chinese Volunteers

et al. 2022

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Background: Ticagrelor belongs to a new class of P2Y12 receptor inhibitor that has been widely used for antiplatelet therapy. This study aimed to explore the effect of single nucleotide polymorphisms (SNPs) in metabolic enzymes, transporters, and other relevant variants on the pharmacokinetics (PK) of ticagrelor and its active metabolite, AR-C124910XX.Methods: The study population comprised 68 healthy Chinese volunteers who were enrolled in a ticagrelor bioequivalence clinical trial. The PK profile of ticagrelor was evaluated after orally administering a single 90-mg dose of ticagrelor in tablet form. The plasma concentrations of ticagrelor and AR-C124910XX were determined through liquid chromatography–tandem mass spectrometry. Plasma DNA samples were used to explore the effect of gene polymorphisms on the PK of ticagrelor and AR-C124910XX with whole-exome sequencing.Results: Female participants had a higher maximum plasma concentration/weight ratio (Cmax/W; p < 0.001) and a shorter half-life (T1/2; p < 0.05) for ticagrelor than their male counterparts. In addition, a higher area under the curve/weight ratio (AUC/W; p < 0.001), and longer T1/2 (p < 0.001) and time to reach the maximum plasma concentration (Tmax; p < 0.001), as well as a lower apparent drug clearance (CL/F; p < 0.001), were observed among healthy volunteers in the fed trial compared to those enrolled in the fasting trial. For AR-C124910XX, higher Cmax/W (p < 0.001) and AUC/W (p < 0.001) but lower CL/F (p < 0.001) and apparent volume of distribution (Vd/F; p < 0.001) were observed among female participants. Healthy volunteers enrolled in the fasting trial exhibited higher Cmax/W (p < 0.001) and AUC/W (p < 0.01), shorter Tmax (p < 0.001), and lower CL/F (p < 0.001) and Vd/F (p < 0.001) than those enrolled in the fed trial. Upon confirmation through multivariate analysis, the CYP4F2 rs2074900 A/A carriers were associated with higher Cmax/W and AUC/W and lower CL/F and Vd/F than the CYP4F2 rs2074900 A/G and G/G carriers.Conclusion: This study is the first to show that the CYP4F2 rs2074900 SNP had a remarkable effect on ticagrelor PK, which is significant since it adds to the limited pharmacogenetic information on ticagrelor.

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Effect of CYP3A4 metabolism on sex differences in the pharmacokinetics and pharmacodynamics of zolpidem

Cited by 32 publications

References 33 publications

Differential sleep/wake response and sex differences following acute suvorexant, MK‐1064 and zolpidem administration in the rTg4510 mouse model of tauopathy

Differential sleep/wake response and sex differences following acute suvorexant, MK‐1064 and zolpidem administration in the rTg4510 mouse model of tauopathy

Therapeutic Drug Monitoring of Lurasidone in Patients with Schizophrenia or Bipolar Disorder: A preliminary study

Effect of CYP4F2 Polymorphisms on Ticagrelor Pharmacokinetics in Healthy Chinese Volunteers

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