Voriconazole and fluconazole increase the exposure to oral diazepam

Objective We assessed the effect of voriconazole and fluconazole on the pharmacokinetics and pharmacodynamics of diazepam. Methods Twelve healthy volunteers took 5 mg of oral diazepam in a randomised order on three study sessions: without pretreatment, after oral voriconazole 400 mg twice daily on the first day and 200 mg twice daily on the second day, or after oral fluconazole 400 mg on the first day and 200 mg on the second day. Plasma concentrations of diazepam and N-desmethyldiazepam were determined for up to 48 h. Pharmacodynamic variables were measured for 12 h. Results In the voriconazole phase, the area under the plasma concentration time curve of diazepam was increased (geometric mean ratio) 2.2-fold (p < 0.05; 90% confidence interval [CI] 1.56 to 2.82). This was associated with the prolongation of the mean elimination half-life (t_1/2) from 31 h to 61 h (p < 0.01) after voriconazole. In the fluconazole phase, the of diazepam was increased 2.5-fold (p < 0.01; 90% CI 1.94 to 3.40), and the t_1/2 was prolonged from 31 h to 73 h (p < 0.001). The peak plasma concentration of diazepam was practically unchanged by voriconazole and fluconazole. The pharmacodynamics of diazepam were changed only modestly. Conclusion Both voriconazole and fluconazole considerably increase the exposure to diazepam. Recurrent administration of diazepam increases the risk of clinically significant interactions during voriconazole or fluconazole treatment, because the elimination of diazepam is impaired significantly.     

Oral voriconazole and miconazole oral gel produce comparable effects on the pharmacokinetics and pharmacodynamics of etoricoxib

Purpose  The effect of topical miconazole oral gel and systemic oral voriconazole on the pharmacokinetics of oral etoricoxib was studied in 12 healthy volunteers. Methods  Plasma concentrations of etoricoxib, miconazole, voriconazole, and thromboxane B₂ generation were followed after ingestion of 60 mg etoricoxib without pretreatment, after topical administration of miconazole oral gel (85 mg × 3, 3 days), or after oral voriconazole (400 mg × 2, 1st day, 200 mg × 2, 2nd day). Results  Etoricoxib area under the plasma concentration-time curve and maximum plasma concentration (C_max) geometric mean ratios (GMR) with/without miconazole were 1.69 {90% confidence interval (CI); 1.46–1.92} and 1.12 (90% CI; 0.99–1.25), respectively, and corresponding GMRs with/without voriconazole were 1.49 (90% CI; 1.37–1.61) and 1.19 (90% CI; 1.08–1.31), respectively. Conclusions  Miconazole oral gel and oral voriconazole produced comparable increase in the exposure to etoricoxib, presumably via CYP3A inhibition.     

Effect of cytochrome P-450 inhibitors on pharmacokinetics and safety of voriconazole

Our objective was to systematically assess the effect of cytochrome P-450 (CYP450) inhibitors on pharmacokinetics and safety of voriconazole (VORI). Cochrane Library, PubMed, Embase, CNKI, CBM and WanFang databases and Clinicaltrials. gov were searched up to Jan. 26th 2016. Two reviewers independently identified studies, extracted data and assessed quality of studies. Meta-analysis was performed with RevMan 5.3, and risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs) were calculated. A total of 12 studies were included: three crossover randomized controlled trials, three single-arm before-and-after studies and six cohort studies. Compared with non-combination group, the group of VORI plus omeprazole had a significantly higher occurrence of hepatic dysfunction (RR = 4.11, 95% CI 1.12–15.08, P = 0.03). However, neurologic dysfunction and visual disturbance were not significantly different. Pantoprazole, rabeprazole, cimetidine and contraceptive significantly increased the peak concentration (Cmax) and area under the curve (AUC) of VORI, while indinavir had no significant effect on pharmacokinetics of VORI. The effects of esomeprazole, erythromycin and azithromycin on pharmacokinetic parameters of VORI presented inconsistent results. Co-administration of VORI and CYP450 inhibitors was safe except for omeprazole. Although Cmax and AUC of VORI were increased while co-administered with a couple of CYP450 inhibitors, no significant effect on clinical outcomes was observed.     

Effect of voriconazole on the pharmacokinetics and pharmacodynamics of zolpidem in healthy subjects

AIMS: To assess the effect of voriconazole on the pharmacokinetics and pharmacodynamics of zolpidem. METHODS: In a randomized cross-over study with two phases, 10 healthy subjects ingested 10 mg of zolpidem with or without oral voriconazole pretreatment. The concentrations of zolpidem were measured in plasma up to 24 h and pharmacodynamic variables were monitored for 12 h. RESULTS: Voriconazole increased the peak plasma concentration of zolpidem by 1.23-fold [P < 0.05; 90% confidence interval (CI) 1.05, 1.45] and the area under the plasma zolpidem concentration-time curve by 1.48-fold (P < 0.001; 90% CI 1.29, 1.74). The time to peak plasma zolpidem concentration was unchanged by voriconazole but the half-life was prolonged from 3.2 to 4.1 h (P < 0.01; 95% CI on the difference 0.27, 1.45). The pharmacodynamics of zolpidem were unaffected by voriconazole. CONCLUSION: Voriconazole caused a moderate increase in exposure to zolpidem in healthy young subjects but no clear pharmacodynamic changes were observed between the groups.     

Voriconazole drastically increases exposure to oral oxycodone

Objective  We investigated the effect of voriconazole on the pharmacokinetics and pharmacodynamics of oxycodone. Methods  Twelve healthy subjects ingested either voriconazole or placebo for 4 days in a randomized, cross-over study. On day 3, they ingested 10 mg oxycodone. Timed plasma samples were collected for the measurement of oxycodone, noroxycodone, oxymorphone, noroxymorphone and voriconazole up to 48 h, and pharmacodynamic effects were recorded. Results  When voriconazole was taken at the same time as oxycodone, the mean area under the plasma concentration-time curve (AUC_0–∞) of oxycodone increased 3.6-fold (range 2.7- to 5.6-fold), peak plasma concentration 1.7-fold and elimination half-life 2.0-fold (p < 0.001) when compared to placebo. The AUC_0-∞ ratio of noroxycodone to oxycodone was decreased by 92% (p < 0.001), and that of oxymorphone increased by 108% (p < 0.01). Pharmacodynamic effects of oxycodone were modestly increased by voriconazole. Conclusions  Voriconazole inhibits the CYP3A-mediated N-demethylation of oxycodone, drastically increasing exposure to oral oxycodone. Clinically, lower doses of oxycodone may be needed during voriconazole treatment to avoid opioid-related adverse effects especially after repeated dosing.     

Effect of route of administration of fluconazole on the interaction between fluconazole and midazolam

Objective: Midazolam is a short-acting benzodiazepine hypnotic extensively metabolized by CYP3A4 enzyme. Orally ingested azole antimycotics, including fluconazole, interfere with the metabolism of oral midazolam during its absorption and elimination phases. We compared the effect of oral and intravenous fluconazole on the pharmacokinetics and pharmacodynamics of orally ingested midazolam. Methods: A double-dummy, randomized, cross-over study in three phases was performed in 9 healthy volunteers. The subjects were given orally fluconazole 400 mg and intravenously saline within 60 min; orally placebo and intravenously fluconazole 400 mg; and orally placebo and intravenously saline. An oral dose of 7.5 mg midazolam was ingested 60 min after oral intake of fluconazole/placebo, i.e. at the end of the corresponding infusion. Plasma concentrations of midazolam, α-hydroxymidazolam and fluconazole were determined and pharmacodynamic effects were measured up to 17 h. Results: Both oral and intravenous fluconazole significantly increased the area under the midazolam plasma concentration-time curve (AUC_0–3, AUC_0–17) 2- to 3-fold, the elimination half-life of midazolam 2.5-fold and its peak concentration (C_max) 2- to 2.5-fold compared with placebo. The AUC_0–3 and the C_max of midazolam were significantly higher after oral than after intravenous administration of fluconazole. Both oral and intravenous fluconazole increased the pharmacodynamic effects of midazolam but no differences were detected between the fluconazole phases. Conclusion: We conclude that the metabolism of orally␣administered midazolam was more strongly inhibited by oral than by intravenous administration of fluconazole. Received: 1 July 1996 / Accepted in revised form: 4 September 1996     

氟康唑与伏立康唑治疗念珠菌肺炎的疗效比较

目的 比较伏立康唑与氟康唑治疗肺部念珠菌感染的疗效与安全性.方法 79例肺念珠菌感染患者按照住院号顺序分为伏立康唑组与氟康唑组,观察患者症状和体征变化,评价感染治愈率及治疗安全性.结果 伏立康唑组总体有效率为93.1％,明显高于氟康唑组的65.9％(x2=7.51,P＜0.01),痊愈率分别为65.1％和36.1％,差异均有统计学意义(x2 =6.60,P＜0.05).伏立康唑组不良反应发生率为14.0％,氟康唑组不良反应发生率为16.7％,两组差异无统计学意义(P＞0.05).结论 伏立康唑治疗肺部念珠菌感染效果优于氟康唑,两者安全性均较高.     

Quercetin pretreatment increases the bioavailability of pioglitazone in rats: involvement of CYP3A inhibition

Herbal antidiabetic preparations are often used as an add-on therapy in diabetes and such herbal preparations often contains quercetin that can inhibit cytochrome P450 (CYP) 3A4. This enzyme is responsible for metabolizing pioglitazone, a commonly used antidiabetic agent. Hence, it was speculated that quercetin may influence the bioavailability of pioglitazone, which could be particularly crucial, as any increment in its plasma levels may raise safety concerns. Thus, we first established the inhibitory influence of quercetin (2, 10 and 20 mg/kg, p.o.) on CYP3A activity by an in vivo method of estimating levels of midazolam in female rats pretreated with dexamethasone. It was further confirmed in vitro using erythromycin-N-demethylase (EMD) assay. These studies indicated potent inhibition of CYP3A activity by quercetin (10 and 20 mg/kg, in vivo; 1 and 10 microM, in vitro). In another experiment, pioglitazone was administered orally (10 mg/kg) and intravenously (5mg/kg) to quercetin (10 mg/kg) pretreated female rats and its plasma levels were determined at various time points (0.5, 1, 2, 4, 8 and 24 h after oral administration; 0.083, 0.5, 1, 2, 8, 12 and 18 h after i.v. administration) by HPLC. Quercetin pretreatment increased AUC(0-infinity) of pioglitazone after oral administration by 75% and AUC(0-infinity) after intravenous administration by 25% suggesting decreased metabolism, which could be due to inhibition of CYP3A by quercetin. In conclusion, add-on preparations containing quercetin may increase the bioavailability of pioglitazone, and hence should be cautiously used.     

Effect of atorvastatin on the intravenous and oral pharmacokinetics of verapamil in rats

The present study aimed to investigate the effect of atorvastatin on the intravenous and oral pharmacokinetics of verapamil in rats. The pharmacokinetic parameters of verapamil were measured after an oral (9 mg/kg) or intravenous (3 mg/kg) administration of verapamil to rats in the presence and absence of atorvastatin. Compared with the control given verapamil alone, the concurrent use of 1.5 mg/kg of atorvastatin significantly increased the oral exposure of verapamil in rats. The AUC and C(max) of verapamil increased by 70% and 61%, respectively in the presence of atorvastatin (1.5 mg/kg), while there was no significant change in T(max) and the terminal plasma half-life (T(1/2)) of verapamil. Accordingly, the presence of atorvastatin significantly (p<0.05) increased the bioavailability of verapamil in rats. In contrast, atorvastatin had no effect on any pharmacokinetic parameters of verapamil given intravenously, implying that atorvastatin may improve the oral bioavailability of verapamil by reducing the prehepatic extraction of verapamil most likely mediated by P-gp and/or CYP3A4. In conclusion, coadministration of atorvastatin significantly enhanced the oral exposure of verapamil in rats without a change in the systemic clearance of intravenous verapamil, suggesting a potential drug interaction between verapamil and atorvastatin via the modulation of prehepatic extraction.     

Influence of voriconazole on pharmacokinetics and safety of combined drugs: a systematic review

We performed a systematic review to evaluate pharmacokinetics changes of drugs when concomitantly used with voriconazole, including randomized controlled trials (RCTs), randomized cross-over trials, self-controlled before-and-after studies, cohort studies and case reports. Literature databases, including Medline, Embase, Cochrane library, were searched to identify eligible studies (until Jan, 2016). A modified risk of bias tool specially developed in this research was used to evaluate the quality of pharmacokinetic randomized crossover trials and self-controlled before-and-after studies. Cochrane risk of bias tool provided by Cochrane Library and Cochrane Reviewer’s handbook was used to evaluate the quality of RCTs and non-randomized controlled studies. Pharmacokinetic parameters, such as area under curve (AUC), C_min, and C_max before and after using voriconalzole were collected. Meta-analysis was conducted to synthesize results if possible. Among 41 studies included in our search, 17 were randomized crossover trials, 3 were RCTs, 13 were self-controlled before-and-after study (SBAs), 1 was cohort studies and 7 were case reports. A total of 12 classes of drugs were involved, including opiates, non-steroidal anti-inflammatory drugs (NSAIDs), psychopathic drugs, anti-HIV drugs, immunosuppressors, oral contraceptive, digoxin, warfarin, oral hypoglycemic agents, antihypertensive agents, lipid regulating agents and cytotoxic agents. According to our results, the impacts of voriconazole on tilidine, buprenorphine, etoricoxib, meloxicam, venlafaxine, midazolam, zolpidem, etravirine and sirolimus were different from the package insert. Our systematic review provided comprehensive data on the pharmacokinetics changes of drugs when used in combination with voriconazole.     

伏立康唑人体药代动力学的特征与差异研究

目的:研究健康受试者口服伏立康唑的药代动力学特征和差异.方法:70名健康志愿者单次口服伏立康唑200 mg后,用HPLC-MS/MS方法测定血中的伏立康唑浓度,分析不同个体伏立康唑的体内代谢过程与动力学差异.结果:伏立康唑药代动力学个体差异很大.其代谢特征可分为四种类型,A型占21%,达峰时间最短,而峰浓度最高,分布容积最小,属于快分布型;B型占53%,所有参数均为中间水平;C型占11%,为慢代谢型;D型占14%,峰浓度最低,达峰时间最晚,AUC最低,清除最快,为强代谢型.结论:伏立康唑个体代谢差异很大,需要进行血药浓度监测.     

CYP3A4基因多态性对健康受试者体内替硝唑药代动力学的影响（英文）

研究中国汉族人群CYP3A4^*18B基因多态性的频率,并探讨CYP3A4^*18B基因多态性对替硝唑药代动力学的影响。本研究共招募100名来自中国汉族的健康志愿者,采用PCR-RFLP方法检测CYP3A4^*18B的基因多态性。选择CYP3A4^*1/^*1(n=10)野生型受试者和CYP3A4^*1/^*18B(n=9)突变杂合型受试者进行替硝唑的药代动力学研究。单剂量口服替硝唑片剂后采集72h内的血样,使用高效液相色谱法测定血浆样本中替硝唑的浓度。发现88名健康志愿者携带CYP3A4^*1/^*1基因型,12人携带CYP3A4^*1/^*18B基因型,未发现携带CYP3A4^*18B/^*18B基因型。CYP3A4^*18B等位基因频率为6%。CYP3A4*1/*1基因型和CYP3A4^*     

盐酸小檗碱对大鼠肝微粒体细胞色素P450酶含量及活性的影响

目的考察盐酸小檗碱对大鼠肝微粒体的蛋白含量、CYP450酶总量和主要CYP450酶亚型(CYP1A2、CYP2D6、CYP3A4和CYP2C19)活性的影响。方法以溶剂为空白对照灌胃给予盐酸小檗碱250 mg/(kg·d),连续7 d,测定其肝微粒体蛋白含量、CYP450蛋白含量以及CYP1A2、CYP2D6、CYP3A4和CYP2C19活性。结果与空白对照组比较,盐酸小檗碱给药组大鼠肝微粒体蛋白含量及肝微粒体CYP450含量无明显差异(P>0.05)。盐酸小檗碱给药后,给药组大鼠的平均CYP3A4活性是空白对照组的1/2;而两组之间CYP1A2、CYP2D6和CYP2C19的活性相当。结论盐酸小檗碱对大鼠CYP3A4活性有一定抑制作用,对CYP1A2、CYP2D6和CYP2C19的活性没有影响。     

The effect of ketoconazole on the pharmacokinetics, pharmacodynamics and safety of nisoldipine

Objective: The primary aim of the present study was to investigate the effect of ketoconazole on the pharmacokinetics of nisoldipine. Methods: A single dose of nisoldipine 5 mg immediate-release tablet was administered either alone or in combination with ketoconazole 200 mg (4 days pre-treatment and concomitant administration) in a randomized crossover trial in seven healthy male Caucasian volunteers. Plasma concentration-versus-time profiles of nisoldipine and its metabolite M9 were determined. Results: Pre-treatment with and concomitant administration of ketoconazole resulted in a 24-fold and 11-fold, increase in mean AUC and C_max of nisoldipine, respectively, compared with treatment with nisoldipine 5 mg alone. The ketoconazole-induced increase in plasma concentration of the metabolite M9 was of similar magnitude. Conclusion: The interaction is attributed to inhibition of cytochrome 3A4-mediated first-pass metabolism. Ketoconazole and other antifungal drugs of the substituted imidazole type as well as other potent inhibitors of cytochrome 3A4 should not be used concomitantly with nisoldipine. Received: 8 September 1998 / Accepted in revised form: 23 November 1998     

Effects of fluconazole on the pharmacokinetics and pharmacodynamics of antimony in cutaneous leishmaniasis-infected hamsters

Pentavalent antimony (Sb^V) compounds are the drugs of choice for the treatment of all forms of leishmaniasis. For 20 years there has been an interest in antifungal azoles for treating leishmaniasis, with variable success. In the current study, we examined the effects of co-administration of fluconazole (FLZ) on the pharmacokinetics and pharmacodynamics of Sb^V in cutaneous leishmaniasis-infected hamsters. Hamsters were divided into four groups. All hamsters were injected with 0.1 mL of 1 × 10⁸ promastigotes/mL into the right foot on Day 1. Treatment was started 5 days after the infection. The antimony group received 80 mg/kg/day of Pentostam^® intramuscularly whilst the FLZ group received FLZ 20 mg/kg/day orally for 14 days. The combination group received both Pentostam^® and FLZ at the above mentioned doses for 14 days. Animals in the control group received no treatment. The infected footpads were measured on Days 1 and 14. A pharmacokinetic study was conducted on Days 1 and 14 of treatment, representing single- and multiple-dose pharmacokinetics, respectively. Blood samples were collected at different time intervals up to 24 h. Sb^V was determined using flameless atomic absorption spectrophotometry. Pharmacokinetic parameters were calculated using a non-compartmental analysis. In the single-dose study, there was no statistically significant difference in any of the pharmacokinetic parameters of Sb^V when given alone or with FLZ. However, on Day 14 a significant increase in peak plasma concentration (C_max) (three-fold) and area under the concentration–time curve (AUC) (four-fold) of antimony was observed when Sb^V was co-administered with FLZ. A statistically significant prolongation of the terminal half-life from 1.63 to 8.67 h (P < 0.05) was also observed. A significant reduction in clearance was detected. However, FLZ had no effect on the pharmacodynamics of Sb^V as measured by footpad sizes. In conclusion, FLZ did not improve the therapeutic effect of Sb^V when given concomitantly despite the significant increase in blood concentration and prolongation of the elimination half-life of Sb^V.     

Expression,Activity and Regulation of CYP3A in Human and Rodent Brain

The importance of cytochrome P450 (CYP) 3A enzymes in human drug metabolism is well established. The function of these enzymes has been characterized extensively in liver and intestinal tissues but much less is known about their expression, regulation and functional activity in the brain. Several lines of evidence point to the presence and function of multiple forms of CYP enzymes, including CYP3A, in both human and rodent brain. Expression studies suggest that CYP3A enzymes show regional differences in their distribution in the brain, where they may play a role in steroid metabolism. They also metabolize many psychoactive drugs and may have a profound effect on their efficacy and safety. This review explores the tissue, cellular, and subcellular expression of CYP3A isoforms in human and rodent brain and provides insight into their functional roles and regulation.     

Differential expression of CYP3A12 and CYP3A26 mRNAs in canine liver and intestine

The cytochrome P450 (CYP) 3A family is often considered the most important CYP subfamily with regard to drug metabolism in people. Certainly, CYP3A4 contributes to poor oral bioavailability of a number of drugs, and a tremendous amount of effort has been made in attempting to find an appropriate model system to predict the oral bioavailability of candidate drugs. The dog is a species widely used as a preclinical model for the evaluation of drug safety and pharmacokinetics. Compared with other species, little information is available on the tissue distribution of CYP enzymes. The purpose of this study was to determine the level of messenger RNA (mRNA) expression of the canine CYP3A subfamily (CYP3A12 and CYP3A26) in the liver and duodenum. Overall, expression of CYP3A mRNA was greater in the liver than in the duodenum. Hepatic expression of CYP3A26 was greater than CYP3A12 in all dogs, with CYP3A26 comprising 75.2% of the hepatic mRNA CYP3A pool. Conversely, duodenal expression of CYP3A12 was greater than CYP3A26 in all dogs, with CYP3A12 comprising 99.8% of the duodenal mRNA CYP3A pool. In summary, these results represent an important step toward the systematic comparison of human and canine CYP3A enzymes, particularly in relation to oral bioavailability of substrate drugs.     

Effect of <Emphasis Type="Italic">CYP3A5*3</Emphasis> genotype on the pharmacokinetics and antiplatelet effect of clopidogrel in healthy subjects

Objective Clopidogrel is activated by cytochrome P450 3A (CYP3A) to generate an active metabolite that inhibits adenosine diphosphate (ADP)-induced platelet aggregation through irreversible binding to the platelet P2Y12 receptor. The objective of this study was to assess the effect of the CYP3A5 genotype on the pharmacokinetics and antiplatelet effect of clopidogrel in healthy subjects. Methods Twenty-two healthy subjects (CYP3A5*1/*1, n = 6; CYP3A5*1/*3, n = 8; CYP3A5*3/*3, n = 8) were recruited. After the administration of a loading dose of 300 mg of clopidogrel followed by 75 mg once daily for 6 days, plasma concentrations of clopidogrel and SR26334, an inactive metabolite, were measured for 24 h. The antiplatelet effect of clopidogrel was also measured, by determining the inhibition of ADP-induced platelet aggregation for 168 h, according to CYP3A5 genotype. Results Mean plasma concentration profiles of clopidogrel and SR26334 were comparable between CYP3A5 genotype groups. In addition, the CYP3A5 genotype did not affect the pharmacokinetics of either clopidogrel or SR26334. CYP3A5 genotype also did not modulate the inhibitory effect of clopidogrel on platelet aggregation. Conclusion The CYP3A5*3 genotype plays a minor role in causing interindividual variability of the disposition of clopidogrel and its antiplatelet effect in humans.     

Nonionic surfactants are strong inhibitors of cytochrome P450 3A biotransformation activity in vitro and in vivo

Nonionic surfactants are commonly used as excipients in pharmaceutical formulation, but recent studies demonstrate that the ingredients affect the pharmacokinetics of the active drugs. However, the mechanisms are largely unknown. Here, we examined the effects of four common nonionic surfactants polysorbate 20, polyoxyl 35 castor oil, polyoxyl 40 stearate and poloxamer 188, on cytochrome P450 3A in vitro and in vivo using midazolam as a probe. We first examined the effects of these surfactants on the 1′-hydroxylation of midazolam in isolated rat liver and intestinal microsomes. All the surfactants tested inhibited midazolam 1′-hydroxylation in a concentration-dependent manner and presented a mixed competitive inhibitory model with decreased V_max and increased K_m values in vitro. Among the tested nonionic surfactants, polysorbate 20 was the most potent inhibitor of midazolam 1′-hydroxylation with an IC₅₀ of 2.06 and 0.39 mg ml⁻¹ in the liver and intestinal microsomes, respectively. These surfactants were also tested in vivo as we investigated their effects on the pharmacokinetics of midazolam in rats. These four surfactants displayed different inhibitory patterns in terms of the AUC of midazolam and 1′-hydroxymidazolam. Polysorbate 20 significantly increased both AUC_0–4 h and AUC_0–∞ of midazolam and decreased the AUC_0–4 h of 1′-hydroxymidazolam to about 40% (p < 0.05) in both single- and multiple-treated rats, along with a significant decrease of the metabolic ratio of 1′-hydroxymidazolam/midazolam to 25%. Polyoxyl 35 castor oil, polyoxyl 40 stearate and poloxamer 188 displayed complicated inhibition on the 1′-hydroxylation of midazolam dependent on the administration formula. These results confirmed that effects of these surfactants would have potential inhibitory effects on cytochrome P450 3A and altered midazolam bioavailability. Therefore, caution is needed when selecting nonionic surfactants in drug formulation.