Mechanism of cytochrome P450-3A inhibition by ketoconazole

Objectives Ketoconazole is extensively used as an index inhibitor of cytochrome P450‐3A (CYP3A) activity in vitro and in vivo, but the mechanism of ketoconazole inhibition of CYP3A still is not clearly established. Methods Inhibition of metabolite formation by ketoconazole (seven concentrations from 0.01 to 1.0 µm ) was studied in human liver microsomes (n = 4) at six to seven substrate concentrations for triazolam, midazolam, and testosterone, and at two substrate concentrations for nifedipine. Key findings Analysis of multiple data points per liver sample based on a mixed competitive–noncompetitive model yielded mean inhibition constant K_i values in the range of 0.011 to 0.045 µm . Ketoconazole IC50 increased at higher substrate concentrations, thereby excluding pure noncompetitive inhibition. For triazolam, testosterone, and midazolam α‐hydroxylation, mean values of α (indicating the ‘mix’ of competitive and noncompetitive inhibition) ranged from 2.1 to 6.3. However, inhibition of midazolam 4‐hydroxylation was consistent with a competitive process. Determination of K_i and α based on the relation between 50% inhibitory concentration values and substrate concentration yielded similar values. Pre‐incubation of ketoconazole with microsomes before addition of substrate did not enhance inhibition, whereas inhibition by troleandomycin was significantly enhanced by pre‐incubation. Conclusions Ketoconazole inhibition of triazolam α‐ and 4‐hydroxylation, midazolam α‐hydroxylation, testosterone 6β‐hydroxylation, and nifedipine oxidation appeared to be a mixed competitive–noncompetitive process, with the noncompetitive component being dominant but not exclusive. Quantitative estimates of K_i were in the low nanomolar range for all four substrates.     

Estimation of Intragastric Solubility of Drugs: In What Medium?

Purpose To measure the solubility of four drugs in human gastric aspirates, canine gastric aspirates (CGF) and simulated gastric fluids in order to propose a medium for estimating intragastric drug solubility relevant to a bioavailability study in the fasted state. Materials and Methods Intragastric environment after administration of water to healthy fasted adults and to healthy fasted dogs (this study) was initially characterized. Solubilities were then measured with the shake-flask method in gastric fluid aspirated after the administration of water to healthy fasted adults and to healthy fasted dogs, in various simulated gastric fluids, i.e. SGF_SLS, SGF_Triton, FaSSGF, FaSSGF_NaCl, and in various HCl solutions with pH values ranging from 1.2 to 2.9. Results In all cases, FaSSGF performed better than canine aspirates, SGF_SLS, SGF_Triton, or FaSSGF_NaCl in predicting solubility in HGF. However, its superiority over HCl pH 1.6 was not clear. For ketoconazole, dipyridamole, miconazole, and felodipine deviations of solubility data in FaSSGF from solubility data in HGF were non-significant, 34, −39 and 252%, respectively, whereas the corresponding deviations of data in HCl pH 1.6 from data in HGF were non-significant, 24, 70, and 130%, respectively. Conclusions Combining data in FaSSGF and HCl pH 1.6 is comparatively the most efficient way to get an estimate of drug solubility in the fasting gastric contents during a bioavailability study. However, accurate estimation of intragastric solubility is limited by the changing environment during intragastric residence of solid particles and the degree of simulation of intragastric composition.     

The effect on sotrastaurin pharmacokinetics of strong CYP3A inhibition by ketoconazole

AIMS

Sotrastaurin is an immunosuppressant that reduces T-lymphocyte activation via protein kinase C inhibition. The effect of CYP3A4 inhibition by ketoconazole on the pharmacokinetics of sotrastaurin, a CYP3A4 substrate, was investigated.

METHODS

This was a two-period, single-sequence crossover study in 18 healthy subjects. They received a single 50 mg oral dose of sotrastaurin in period 1 followed by a 14-day inter-treatment phase. In period 2 they received ketoconazole 200 mg twice daily for 6 days and a single 50 mg dose of sotrastaurin on the fourth day of ketoconazole administration.

RESULTS

Co-administration of single-dose sotrastaurin during steady-state ketoconazole increased sotrastaurin C_max by 2.5-fold (90% confidence interval 2.2, 2.9) from 285 ± 128 to 678 ± 189 ng ml⁻¹ and increased AUC by 4.6-fold (4.1, 5.2) from 1666 ± 808 to 7378 ± 3011 ng ml⁻¹ h. Sotrastaurin half-life was nearly doubled from 5.9 ± 1.7 to 10.6 ± 2.5 h. The AUC of the active metabolite N-desmethyl-sotrastaurin was increased by 6.8-fold. Sotrastaurin did not alter ketoconazole steady-state predose plasma concentrations.

CONCLUSIONS

The strong CYP3A4 inhibitor ketoconazole increased sotrastaurin AUC by 4.6-fold. A compensatory reduction in the dose of sotrastaurin is warranted when strong CYP3A4 inhibitors are co-administered.     

Flutrimazole shampoo 1% versus ketoconazole shampoo 2% in the treatment of pityriasis versicolor. A randomised double-blind comparative trial

Flutrimazole is an imidazole derivative that has been proven to be efficient in superficial skin fungal infections. The aim of this randomised double-blind study was to compare for the first time, the efficiency and safety of flutrimazole 1% shampoo versus ketoconazole 2% shampoo in the treatment of tinea versicolor. Study population consisted of 60 patients with pityriasis versicolor diagnosed clinically and through direct microscopy and culture. Patients were randomly assigned to two groups: one instructed to apply flutrimazole shampoo 1% and one instructed to apply ketoconazole shampoo 2% both on head and body for 14 days. Patients were re-evaluated 14 days after the end of treatment clinically and through direct microscopy and culture. Twenty-one of 26 patients (80.8%) in the ketoconazole and 22 of 29 patients (75.9%) in the flutrimazole group had both visual healing and negative mycological evaluation. Comparison of the response between the two groups with the Yates' corrected chi-square was found statistically not significant (chi(2) = 0.19, d.f. = 1, P = 0.91). None of the patients in the two groups reported any adverse effects. Fourteen (53%) patients in the ketoconazole group and 23 (79%) in the flutrimazole group assessed the shampoos as cosmetically acceptable regarding texture, smell and foam properties. Flutrimazole shampoo 1% appears to present efficacy comparable with ketoconazole 2% in the treatment of tinea versicolor.     

Diclofenac hydroxylation in monkeys: efficiency, regioselectivity, and response to inhibitors

The catalytic efficiency, regioselectivity, and response to chemical inhibitors of diclofenac (DF) hydroxylation in three Old World monkey liver microsomes (rhesus, cynomolgus, and African green monkey) are different from those determined with human liver microsomes. In contrast to the high affinity-high capacity (low Km-high Vmax) characteristics of DF 4'-hydroxylation in humans, this reaction proceeded in all monkey species with catalytic efficiencies >20-fold lower. However, DF 5-hydroxylation, a negligible reaction in human liver microsomes, was kinetically favored in monkeys mainly due to the increased Vmax values. Chemical inhibitors (reversible or mechanism-based) selective to human CYP3A4 and CYP2C9 failed to differentiate monkey orthologs involved in DF hydroxylation. Immunoinhibition studies with monoclonal antibodies against human CYPs revealed the major contribution of CYP2C and CYP3A to 4'- and to 5-hydroxylation, respectively, in rhesus and cynomolgus liver microsomes. However, in African green monkeys, in addition to CYP2C, CYP3A also appeared to be involved in 4'-hydroxylation. Further studies with recombinant rhesus and African green monkey CYP2C and CYP3A enzymes (rhesus CYP2C75, 2C74, and 3A64; African green monkey CYP2C9agm and CYP3A4agm) confirmed the major role of CYP enzymes of these two subfamilies in DF 4'- and 5-hydroxylation. Clearly, while monkey CYP2C and 3A enzymes retain the same substrate selectivity towards DF hydroxylation as their human orthologs, their altered catalytic efficiency and response to chemical inhibitors may indicate different structural features of active sites as opposed to human orthologs.     

三唑类抗真菌药物致急性胰腺炎不良反应文献分析

目的 探讨三唑类抗真菌药物致急性胰腺炎不良反应的临床特点、发生机制及防治措施,为临床合理用药提供参考。方法 检索三唑类抗真菌药物自上市以来国内外发表的关于其引起急性胰腺炎不良反应的文献,按照患者性别、年龄、饮酒史、用药情况、不良反应发生的时间、临床表现及处理方法等进行统计分析。结果 共纳入8篇文献,涉及11例患者,18岁以下儿童所占比例最高（36.36%）。不良反应发生时间最短的为用药12 h,最长的为用药10周后,停药或减量或更换药品后不良反应症状可痊愈或好转。结论 三唑类抗真菌药物致急性胰腺炎不良反应需引起医务人员重视,尤其是应用于儿童时。建议临床在应用三唑类抗真菌药物时,严格按照说明书的推荐剂量和疗程给药,并密切监测患者是否出现急性胰腺炎的症状。     

双波长分光光度法测定酮康霜的含量

本文介绍了双波长分光光度法测定酮康霜的含量,其方法简便可行。回收率为99.73%,RSD为：1.08%,为控制酮康霜质量提供了可靠方法。     

The effect of ketoconazole on the jejunal permeability and CYP3A metabolism of (R/S)-verapamil in humans

AIMS: The purpose of this human intestinal perfusion study was to investigate the effect of ketoconazole on the jejunal permeability and first-pass metabolism of (R)- and (S)-verapamil in humans. METHODS: A regional single-pass perfusion of the jejunum was performed using a Loc-I-Gut(R) perfusion tube in six healthy volunteers. Each perfusion lasted for 200 min and was divided into two periods of 100 min each. The inlet concentration of (R/S)-verapamil was 120 mg l-1 in both periods, and ketoconazole was added at 40 mg l-1 in period 2. (R/S)-verapamil was also administered as a short intravenous infusion of 5 mg, over a period of 10 min. The appearance ratios of the CYP3A formed metabolites (R)- and (S)-norverapamil were also estimated in the outlet jejunal perfusate. RESULTS: The effective jejunal permeability (Peff) of both (R)- and (S)-verapamil was unaffected by the addition of ketoconazole in period 2 suggesting that ketoconazole had no effect on the P-glycoprotein mediated efflux. However, the appearance ratio of both (R)- and (S)-norverapamil in the outlet jejunal perfusate decreased in the presence of ketoconazole. The rate of absorption into plasma of (R)- and (S)-verapamil increased despite the low dose of ketoconazole added, indicating an inhibition of the gut wall metabolism of (R/S)-verapamil by ketoconazole. CONCLUSIONS: Ketoconazole did not affect the jejunal Peff of (R/S)-verapamil, but it did increase the overall transport into the systemic circulation (bioavailability), probably by inhibition of the gut wall metabolism of verapamil. This might be due to ketoconazole being less potent as an inhibitor of P-glycoprotein than of CYP3A4 in vivo in humans.     

氢化可的松对酮康唑经大鼠皮肤透过性的影响

目的研究氢化可的松对酮康唑经大鼠皮肤透过性的影响。方法将12只♂Wistar大鼠随机分为两组,每组6只,分别设置为空白乳膏组和氢化可的松乳膏组,大鼠剃除腹部的毛后分别涂空白乳膏和氢化可的松乳膏,每天1次,连续给药两周(2 g·d-1)。给药结束后取下所有大鼠的腹部皮肤,采用改良的Franz扩散池法比较酮康唑乳膏经两组大鼠腹部皮肤的透过性差异,采用HPLC法检测样品中酮康唑的浓度,将浓度换算得到渗透速率。结果酮康唑乳膏经氢化可的松组大鼠腹部皮肤和空白乳膏组大鼠腹部皮肤的渗透速率分别为(0.403+0.026)和(0.730+0.042)μg·cm-2·h-1,两组实验结果差异有显著性(P<0.01)。结论♂Wistar大鼠腹部皮肤连续使用氢化可的松两周后,可能对皮肤组织产生了影响,从而引起酮康唑经皮透过的改变,导致酮康唑经皮透过量减少,渗透速率降低。这一结果提示,患者在使用氢化可的松乳膏后再使用其他经皮给药制剂时可能需考虑调整剂量。     

萘替芬酮康唑乳膏治疗马拉色菌毛囊炎的临床效果

目的 研究萘替芬酮康唑乳膏治疗马拉色菌毛囊炎的临床效果。方法 选择来宾市人民医院 2020年4月-2021年12月收治的50例马拉色菌毛囊炎患者，按照随机数字表法分为对照组和观察组，各 25例。对照组采用2%硝酸咪康唑乳膏进行治疗，观察组采用萘替芬酮康唑乳膏进行治疗，比较两组临 床疗效、真菌清除率、生活质量及不良反应发生情况。结果 观察组治疗总有效率为96.00%，高于对照 组的76.00%（P＜0.05）；观察组真菌清除率为92.00%，高于对照组的68.00%（P＜0.05）；观察组 精神健康、社会功能、一般健康、生理职能、精力、躯体功能、情感功能、生理功能评分均高于对 照组（P＜0.05）；观察组不良反应发生率为8.00%，略低于对照组的12.00%，但差异无统计学意义（P ＞0.05）。结论 应用萘替芬酮康唑乳膏对马拉色菌毛囊炎患者进行治疗，可有效提升临床疗效以及真菌清 除率，改善患者生活质量，且不增加不良反应。