来曲唑在大鼠体内药代动力学的性别差异(英文)

目的:研究来曲唑(Letr)药动学性别差异性。方法:ig Letr 2mg/kg后,测定在雄、雌性大鼠血浆、组织中浓度及粪、尿中回收率。结果:ig Letr 6 h以后,雄鼠中血药浓度显著低于雌鼠,如给药24,36,48和72h,雌鼠血药浓度分别为雄鼠的3.3,5.6,10.5和7.4倍。雄鼠AUC也仅为雌鼠的1/3,其半衰期分别为10.5和40.4h。120h内,雌鼠尿和粪中排泄分数分别为5.78％±1.40％和6.61％±1.10％,而雄鼠仅分别为1.30％±0.59％和0.87％±0.31％;给药后24h,雌鼠组织中药物浓度显著高于雄鼠。结论:Letr在大鼠体内的药动学存在较大的性别差异。     

三七提取物对大鼠体内他莫昔芬及其代谢物的药动学的影响

目的:研究三七提取物对大鼠体内他莫昔芬及其代谢物的药动学的影响。方法:口服给予大鼠三七提取物10 d后再分别予口服、静注他莫昔芬,采用LC-MS/MS方法,测定他莫昔芬和4-羟基他莫昔芬在血浆和胆汁中的浓度,比较药动学行为的改变情况。结果:三七提取物未改变他莫昔芬及其代谢物的血浆药动学参数,但能明显影响他莫昔芬及其代谢物的口服吸收和胆汁排泄。结论:三七提取物对大鼠体内他莫昔芬及其代谢物的口服吸收和胆汁排泄存在影响,临床上二者合用时应注意潜在的药物相互作用。     

Clinical pharmacokinetics and pharmacogenetics of tamoxifen and endoxifen

Introduction: Tamoxifen dominates the anti-estrogenic therapy in the early and metastatic breast cancer setting. Tamoxifen has a complex metabolism, being mainly metabolized by CYP2D6 into its 30–100 times more potent metabolite, endoxifen. Recently, a phase I study in which endoxifen as an orally z-endoxifen hydrochloride has been successfully evaluated.

Areas covered: the principal pharmacogenetic and non-genetic differences in the pharmacology of tamoxifen and endoxifen are evaluated. To this end, references from PubMed, Embase or Web of Science, among others, were reviewed As non-genetic factors, important differences and similarities such age, or adherence to tamoxifen therapy are comprehensively illustrated. Additionally, since CYP2D6 genotypes are considered the main limitation of tamoxifen, many studies have investigated the association between the worsened clinical outcomes in patients with non-functional CYP2D6 genotypes. In this review, an overview of the research on this field is presented. Also, a summary describing the literature about individualizing tamoxifen therapy with endoxifen concentrations and its limitations is listed.

Expert opinion: z-endoxifen hydrochloride is only investigated in the metastatic setting, still more research is required before its place in therapeutics is known. Similarly, monitoring tamoxifen efficacy based on endoxifen concentrations might not be overall recommended due to the limited evidence available.     

阿霉素对去甲斑蝥素在大鼠体内药动学的影响

目的研究大鼠静脉给予阿霉素（ADM）对去甲斑蝥素（NCTD）体内药物动力学的影响。方法用HPLC-MS方法测定ADM和NCTD合并给药与NCTD单独给药大鼠血浆中的NCTD浓度,比较两者的药动学参数。结果ADM和NCTD合并给药组与NCTD单独给药组相比在分布速度常数（α）、分布相半衰期（t1/2α）、中央室向周边室的转运速度常数（k12）3个药动学参数有统计学差异（P〈0.05）,其余药动学参数之间无显著差异（P〉0.05）。结论NCTD与ADM合用时,ADM不会显著影响NCTD在大鼠体内的药动学过程,两药合用增效的原因主要在于药效学上的协同作用。     

Pharmacological effects and pharmacokinetics properties of Radix Scutellariae and its bioactive flavones

Radix Scutellariae is the dried root of the medicinal plant Scutellariae baicalensis Georgi. It exhibits a variety of therapeutic effects and has a long history of application in traditional formulations as well as in modern herbal medications. It has been confirmed that flavonoids are the most abundant constituents and induce these therapeutic effects. Six flavones are proven to be the major bioactive flavones in Radix Scutellariae existing in the forms of aglycones (baicalein, wogonin, oroxylin A) and glycosides (baicalin, wogonoside, oroxylin A-7-glucuronide). All six flavones are pharmacologically active and show great potential in the treatment of inflammation, cancers and virus-related diseases. The current review covers the preparation of the herb Radix Scutellariae, quantification of its major bioactive ingredients, and pharmacological effects of the proposed six bioactive flavones. In addition, this review summarizes the pharmacokinetic profiles of the bioactive flavones reported so far that could be used for further improvement of their pharmacokinetic study. Moreover, due to abundant co-occurring bioactive components in Radix Scutellariae, our review further documents the pharmacokinetic interactions among them.     

Investigation of the impact of sarizotan on the pharmacokinetics of levodopa

OBJECTIVE: To investigate the effect of sarizotan on the pharmacokinetics of levodopa in fixed combination with carbidopa or benserazide. METHODS: In this open-label, randomized, crossover study, healthy male subjects (n=16) received levodopa 100 mg t.i.d. over two 5-day periods, alone or in combination with sarizotan 5 mg b.i.d. Levodopa was administered with a dopa-decarboxylase inhibitor (carbidopa 25 mg, n=8 or benserazide 25 mg, n=8). Pharmacokinetic parameters of levodopa were obtained on days 1 and 5. RESULTS: ANOVA showed the C(max) values for levodopa were not significantly different with or without sarizotan after single doses (1001 vs 1082 ng/ml; point estimate [PE] 1.10, 90% confidence intervals [CI] 0.83-1.45) or at steady-state (1549 vs 1663 ng/ml; PE 1.06, 90% CI 0.89-1.27); nor were AUC values for single doses (1661 vs 1665 ng h/ml; PE 1.01, 90% CI 0.91-1.11) or at steady-state (2462 vs 2482 ng h/ml; PE 1.01, 90% CI 0.97-1.05). Seven subjects reported adverse events of mild-to-moderate intensity; the most frequent were headaches and dizziness. Conclusion: Coadministration of sarizotan with levodopa, in combination with a dopa-decarboxylase inhibitor had no effect on the pharmacokinetics or adverse event profile of levodopa.     

The quinolone,flumequine, has no effect on theophylline pharmacokinetics

The kinetics of a single i. v. dose of theophylline given either alone or with flumequine was studied in eight healthy volunteers. No statistically significant differences were observed in the pharmacokinetic parameters of theophylline (volume of distribution, elimination half-life, AUC, plasma clearance) following the two treatments.Pretreatment for 5 days with oral flumequine (400 mg, three times daily) had no significant effect on the disposition of a single i. v. dose of theophylline in healthy volunteers.     

林可霉素对庆大霉素药动学的影响

本文运用荧光偏振免疫分析法(FPIA),测定了林可霉素与庆大霉素肌注合并用药前后的5.例受试者庆大霉素血清浓度,数据按单室模型回归分析取得药动学参数,并进行统计学处理,结果发现合并用药前后药动学参数无明显变化(P>0.05)。     

Lack of effect of tofacitinib (CP-690,550) on the pharmacokinetics of the CYP3A4 substrate midazolam in healthy volunteers: confirmation of in vitro data

AIMS

To investigate inhibitive and inductive effects of tofacitinib (CP-690,550), a Janus kinase inhibitor, on CYP3A4 function via in vitro and in vivo studies.

METHODS

In vitro experiments were conducted to assess the inhibition and induction potential of tofacitinib for major drug metabolizing enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4). A phase 1, randomized, open-label, two-way crossover study ({"type":"clinical-trial","attrs":{"text":"NCT00902460","term_id":"NCT00902460"}}NCT00902460) was conducted to confirm the lack of inhibitive/inductive effect on a sensitive CYP3A4 substrate, midazolam, in healthy subjects. Midazolam pharmacokinetics were assessed over 24 h following single dose 2 mg administration prior to administering tofacitinib and after twice daily dosing of tofacitinib 30 mg for 6 days. The primary endpoint was midazolam area under the concentration–time profile, from time 0 to infinity (AUC(0,∞)).

RESULTS

In vitro studies demonstrated low potential for CYP inhibition (IC₅₀ estimates tofacitinib >30 µm), CYP3A4 mRNA induction (observed at tofacitinib concentrations ≥25 µm) and no effect on enzymatic activity of CYP substrates. In the human study, AUC(0,∞) adjusted geometric mean ratio for midazolam plus tofacitinib to midazolam alone was 103.97% [90% confidence interval (CI) 95.57, 113.12], wholly within the pre-specified acceptance region (80, 125). The 90% CI for the ratio of adjusted geometric means of maximum plasma concentration (C_max) (95.98, 108.87) was also wholly within this acceptance region.

CONCLUSIONS

These data confirm a lack of an inhibitive or inductive effect of tofacitinib on CYP3A activity in humans and, in conjunction with in vitro data, support the conclusion that tofacitinib is unlikely to influence the CYP enzyme system as a whole.     

Metronidazole leads to enhanced uptake of imatinib in brain, liver and kidney without affecting its plasma pharmacokinetics in mice

Objectives The pharmacokinetic interaction between metronidazole, an antibiotic–antiparasitic drug used to treat anaerobic bacterial and protozoal infections, and imatinib, a CYP3A4, P‐glycoprotein substrate kinase inhibitor anticancer drug, was evaluated. Methods Male imprinting control region mice were given 50 mg/kg imatinib PO (control group) or 50 mg/kg imatinib PO, 15 min after 40 mg/kg PO metronidazole (study group). Imatinib plasma, brain, kidney and liver concentrations were measured by HPLC and non‐compartmental pharmacokinetic parameters estimated. Key findings Metronidazole coadministration resulted in a double‐peak imatinib disposition profile. The maximum concentration (C_max) decreased by 38%, the area under the curve (AUC_0–∞) decreased by 14% and the time to C_max (T_max) was earlier (50%) in plasma. Apparent volume of distribution (V_SS/F) and oral clearance (Cl/F) increased by 21% and 17%, respectively. Imatinib tissue penetration was higher after metronidazole coadministration, with 1.7 and 2.1‐fold AUC_0–∞ increases in liver and kidney, respectively. Metronidazole increased imatinib's tissue‐to‐plasma AUC_0–∞ ratio in liver from 2.29 to 4.53 and in kidney from 3.04 to 7.57, suggesting higher uptake efficiency. Brain C_max was 3.9‐fold higher than control and AUC_{0–t last} was 2.3‐fold greater than plasma (3.5% in control group). No tissue‐plasma concentration correlation was found. Conclusions Metronidazole slightly decreased imatinib systemic exposure but enhanced liver, kidney and brain penetration, probably due to metronidazole‐mediated inhibition of P‐glycoprotein and other efflux transporters. The high brain exposure opens possibilities for treatment of glioma and glioblastoma. Renal and hepatic functions may need to be monitored due to potential renal and hepatic toxicity.     

大鼠口服尼莫地平吸收动力学性别差异研究

目的 :研究大鼠ig尼莫地平 (NMD)后体内药物动力学是否存在性别差异 ,并考察合用红霉素(Ery)后血浆中NMD变化。方法 :雌性和雄性大鼠单独igNMD或与Ery合用后 ,用HPLC法测定血浆中NMD的浓度。结果 :大鼠ig给药NMD(2 0mg·kg-1) ,雌鼠血浆中的NMD浓度显著高于雄鼠 (P <0 .0 5 ) ,其AUC值是雄鼠的 4 .4倍。合用Ery后 ,与单用比较 ,无论是雄鼠 ,还是雌鼠 ,血浆中NMD浓度显著升高 ,AUC值分别提高了 2 .0和 1.6倍。合用Ery ,NMD的性别差异仍然存在。雌鼠的浓度仍然高于雄鼠 ,AUC值是雄鼠的 3.4倍。结论 :NMD在大鼠体内口服吸收动力学存在性别差异 ,并且红霉素可以提高NMD在血浆中的浓度。     

The effect of CYP3A inhibitors and inducers on the pharmacokinetics of telaprevir in healthy volunteers

AIM

To evaluate the effects of ketoconazole, rifampicin and efavirenz on the pharmacokinetics of telaprevir in healthy volunteers.

METHOD

Results from three clinical studies are described. (1) Volunteers received a single 750 mg dose telaprevir with and without a single 400 mg dose ketoconazole. (2) Volunteers received (a) 1250 mg telaprevir followed by three 750 mg doses given every 8 h and (b) four 1250 mg telaprevir doses given every 8 h, with a single 400 mg dose ketoconazole given with the fourth dose of telaprevir. (3) Volunteers received either a single 750 mg dose telaprevir with or without 600 mg once daily rifampicin, or 750 mg every 8 h telaprevir with and without 600 mg once daily efavirenz.

RESULTS

A single 400 mg dose of ketoconazole increased single dose telaprevir exposure: the geometric least-squares mean ratio (GLSMR, with 90% confidence limits) was 1.24 (1.10, 1.41) for C_max and 1.62 (1.45, 1.81) for AUC(0,∞). However, after multiple doses of telaprevir, there was no discernible effect of ketoconazole on telaprevir exposure. Co-administration of rifampicin at steady-state markedly reduced single dose telaprevir exposure with GLSMRs of 0.14 (0.11, 0.18) for C_max and 0.08 (0.07, 0.11) for AUC(0,∞), whereas efavirenz had a smaller effect on telaprevir exposure when both drugs were co-administered at steady-state, with GLSMRs of 0.91 (0.81, 1.02) for C_max, 0.53 (0.44, 0.65) for C_min, and 0.74 (0.65, 0.84) for AUC(0,8 h).

CONCLUSION

CYP3A inducers, rifampicin and efavirenz, can reduce telaprevir exposure to varying degrees based on their potency. The effect of ketoconazole as an inhibitor of telaprevir metabolism is more pronounced after a single dose of telaprevir than after repeated administration.     

Effects of fesoterodine on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers

AIMS

To confirm the lack of an interaction of fesoterodine 8 mg with warfarin pharmacokinetics and pharmacodynamics in healthy adults.

METHODS

In this open-label, two-treatment, crossover study, subjects (n = 14) aged 20–41 years with normal prothrombin time (PT) and International Normalized Ratio (INR) were randomized to receive a single dose of warfarin 25 mg alone in one period and fesoterodine 8 mg once daily on days 1–9 with a single dose of warfarin 25 mg co-administered on day 3 in the other period. There was a 10-day washout between treatments. Pharmacokinetic endpoints were area under the plasma concentration–time curve from time 0 to infinity (AUC(0,∞)), maximum plasma concentration (C_max), AUC from time 0 to the time of the last quantifiable concentration (AUC(0,last)), time to C_max (t_max), and half-life (t_1/2) for S- and R-warfarin. Pharmacodynamic endpoints were area under the INR-time curve (AUC_INR), maximum INR (INR_max), area under the PT-time curve (AUC_PT) and maximum PT (PT_max).

RESULTS

Across all pharmacokinetic and pharmacodynamic comparisons, the point estimates of treatment ratio (warfarin co-administered with fesoterodine vs. warfarin alone) were 92–100%. The 90% confidence intervals for the ratios of the adjusted geometric means were contained within (80%, 125%). There were no clinically relevant changes in laboratory tests, vital signs or ECG recordings.

CONCLUSIONS

The pharmacokinetics and pharmacodynamics of warfarin 25 mg in healthy adults are unaffected by fesoterodine 8 mg. Concomitant administration of fesoterodine and warfarin was well tolerated.     

Effect of long-term coadministration of compound glycyrrhizin tablets on the pharmacokinetics of mycophenolic acid in rats

1.?Mycophenolic acid (MPA), having high-protein affinity, is an immunodepressant and the genuine-active ingredient of enteric-coated mycophenolate sodium (EC-MPS) tablet that has been widely used in combination with tacrolimus or cyclosporine to prevent acute rejection after organ transplantation. Moreover, MPA mainly experiences glucuronidation and its metabolites are partly transported by multidrug resistance-associated protein (Mrp) 2 into bile then reforms MPA via enterohepatic circulation.

2.?Glycyrrhizin (GL), having high-protein affinity, is the main active ingredient of compound glycyrrhizin tablet, which is often prescribed with EC-MPS, tacrolimus or cyclosporine to prevent drug-induced hepatitis. In addition, GL can inhibit Mrp2 and selectively induce CYP3A and UGTs; and it also undergoes enterohepatic circulation.

3.?After 14 days of coadministration of compound GL tablets with the capsules of EC-MPS tablets, the AUC_0–48?h of total and free MPA was dramatically increased, and the clearance of total and free MPA was apparently decreased. It would seem reasonable that our data appear to support further investigation of this drug–drug interactions in the clinic and more careful monitoring of drug levels as well as clinical effect and toxicity in patients receiving the combination of these two agents.     

Effect Of epigallocatechin-3-gallate on the pharmacokinetics of amlodipine in rats

1. This study investigates the effect of epigallocatechin-3-gallate (EGCG), a major ingredient of green tea, on the pharmacokinetics of amlodipine in rats.

2. The pharmacokinetics of orally administered amlodipine (1?mg/kg) with or without EGCG pretreatment (30?mg/kg/day for 10?days) were investigated. Plasma concentrations of amlodipine were determined by using a sensitive and reliable liquid chromatography with tandem mass spectroscopy (LC-MS/MS) method. The effects of EGCG on the metabolic stability of amlodipine were investigated by using rat liver microsome incubation systems.

3. The results indicated that when the rats were pretreated with EGCG, the C_max of amlodipine increased from 16.32?±?2.57 to 21.44?±?3.56?ng/mL (p?<?0.05), the T_max decreased from 5.98?±?1.25 to 4.01?±?1.02?h (p?<?0.05), and the AUC_0–t increased from 258.12?±?76.25 to 383.34?±?86.95?μg h L^?1 (p?<?0.05), which suggested that the pharmacokinetic behavior of amlodipine was affected after oral co-administration of EGCG. Additionally, the metabolic half-life was prolonged from 31.3?±?5.6 to 52.6?±?7.9?min (p?<?0.05) with the pretreatment of EGCG.

4. It can be speculated that the drug-drug interaction between EGCG and amlodipine might occur, which might have resulted from the metabolism inhibition of amlodipine by EGCG when they were co-administered.

     

Effects of the moderate CYP3A4 inhibitor, fluconazole, on the pharmacokinetics of fesoterodine in healthy subjects

AIMS

To assess the effects of fluconazole, a moderate CYP3A4 inhibitor, on the pharmacokinetics (PK) and safety/tolerability of fesoterodine.

METHODS

In this open-label, randomized, two-way crossover study, 28 healthy subjects (18–55 years) received single doses of fesoterodine 8 mg alone or with fluconazole 200 mg. PK endpoints, including the area under the plasma concentration–time curve from 0 to infinity (AUC(0,∞)), maximum plasma concentration (C_max), time to C_max (t_max), and half-life (t_1/2), were assessed for 5-hydroxymethyl tolterodine (5-HMT), the active moiety of fesoterodine.

RESULTS

Concomitant administration of fesoterodine with fluconazole increased AUC(0,∞) and C_max of 5-HMT by approximately 27% and 19%, respectively, with corresponding 90% confidence intervals of (18%, 36%) and (11%, 28%). There was no apparent effect of fluconazole on 5-HMT t_max or t_½. Fesoterodine was generally well tolerated regardless of fluconazole co-administration, with no reports of death, serious adverse events (AEs) or severe AEs. Following co-administration of fesoterodine with fluconazole, 13 subjects (48%) experienced a total of 40 AEs; following administration of fesoterodine alone, six subjects (22%) experienced a total of 19 AEs. The majority of AEs were of mild intensity. There were no clinically significant changes in laboratory or physical examination parameters.

CONCLUSION

Fesoterodine 8 mg single dose was well tolerated when administered alone or with fluconazole. Based on the observed increase in 5-HMT exposures being within the inherent variability of 5-HMT pharmacokinetics, adjustment of fesoterodine dose is not warranted when co-administered with a moderate CYP3A4 inhibitor provided they are not also inhibitors of transporters.     

来曲唑片在中国健康人体的生物等效性

目的评价国产与进口来曲唑片在中国健康人体的生物等效性。方法24名健康男性受试者随机交叉单剂量口服来曲唑片试验药物或对照药物,各2.5 mg。用液相色谱-串联质谱法测定血浆中来曲唑的浓度;用BAPP 2.0软件计算药代动力学参数,并对2种药物进行生物等效性评价。结果试验药物和对照药物的主要药代动力学参数:Cmax分别为(24.48±5.72)和(26.17±5.55)ng.mL-1;Tmax分别为(1.88±1.04)和(1.98±1.26)h;t1/2分别为(60.04±34.45)和(55.31±23.05)h;AUC0-t分别为(1749.08±859.64)和(1793.65±808.62)ng.h.mL-1。AUC0-t、AUC0-∞、Cmax的90%可信区间分别为92.39%～101.96%;93.08%～104.25%和85.11%～101.82%。试验药物相对于对照药物的生物利用度F为(97.94±13.35)%。结论试验药物和对照药物生物等效。     

tamoxifen对大鼠垂体前叶细胞增殖的抑制作用

目的　观察雌激素受体阻断剂tamoxifen对大鼠垂体前叶细胞增殖的影响。方法　应用大鼠垂体前叶细胞原代培养和3 H TdR参入法检测细胞增殖 ,用电镜观察细胞形态学的改变。结果　tamoxifen能抑制大鼠垂体前叶细胞增殖 ,0 1μmol·L-1tamoxifen的抑制作用可被雌激素反转。 1μmol·L-1tamoxifen作用 4 8h ,细胞出现典型的凋亡改变。结论　tamoxifen抑制大鼠垂体前叶细胞增殖 ,并诱导细胞发生凋亡     

克拉霉素对替硝唑大鼠体内药动学的影响

目的探讨克拉霉素对替硝唑大鼠体内药动学过程的影响。方法大鼠随机分为两组,每组5只,其中一组大鼠灌胃给药替硝唑后测定血浆中药物的质量浓度,另一组灌胃给药克拉霉素,连续5 d,于第6天联合给药替硝唑与克拉霉素,而后测定血浆中替硝唑药物质量浓度,计算药动学参数。用DAS软件程序进行数据处理并采用SPSS软件进行统计学分析。结果单独给药替硝唑组的主要药动学参数为:ρmax为(27.08±2.98)mg.L-1,t1/2为(2.16±0.76)h,AUC0-24 h为(138.04±5.84)mg.h.L-1。联合给药组的替硝唑主要药动学参数为:ρmax为(32.73±8.37)mg.L-1,t1/2为(2.76±1.69)h,AUC0-24 h为(160.45±7.83)mg.h.L-1。其中,两组间AUC及Cl/F存在显著性差异(P<0.05)。结论克拉霉素对替硝唑大鼠体内药动学过程影响较小。     

Effect of metoclopramide and loperamide on the pharmacokinetics of didanosine in HIV seropositive asymptomatic male and female patients

Summary The pharmacokinetics of orally-administered didanosine were evaluated in 6 male and 6 female HIV seropositive patients to determine the effect of pretreatment with metoclopramide, an inducer of gastrointestinal motility, and loperamide, which retards motility. Using a randomized, balanced, crossover design, each patient received the following three treatments under fasting conditions: didanosine as a single agent, didanosine 5 min after a single 10 mg intravenous dose of metoclopramide, and didanosine 1 h after the final of 4 doses, 4 mg each, of loperamide. Serial blood and urine samples were collected for up to 12 h after each dose. Plasma and urine aliquots were analysed for intact didanosine using HPLC with UV detection. Pharmacokinetic parameter values were calculated using noncompartmental methods.The mean C_max values were significantly greater for the didanosine single agent (2.04 g·ml^–1) and didanosine with metoclopramide (2.30 g·ml^–1) treatments than for the combination of didanosine with loperamide (1.57 g·ml^–1). The t_1/2 in males was significantly greater than in females for the didanosine (1.75 vs 1.12 h, respectively) and didanosine with metoclopramide treatments (1.74 vs 1.20 h, respectively). No significant treatment or gender effects were observed for AUC or UR (urinary recovery).The pharmacokinetics of didanosine were not altered appreciably by dosing with metoclopramide. Administration with loperamide affected the rate but not the extent of absorption. There were no clinically relevant differences between males and females in the disposition of didanosine.