The pharmacokinetic study on the interaction between nobiletin and anemarsaponin BII in vivo and in vitro

ContextThe interaction between nobiletin and anemarsaponin BII could affect the pharmacological activity of these two drugs during their combination.ObjectiveThe co-administration of nobiletin and anemarsaponin BII was investigated to explore the interaction and the potential mechanism.Materials and methodsMale Sprague-Dawley rats were only orally administrated with 50 mg/kg nobiletin as the control and another six rats were pre-treated with 100 mg/kg anemarsaponin BII for 7 d followed by the administration of nobiletin. The transport and metabolic stability of nobiletin were evaluated in vitro, and the effect of anemarsaponin BII on the activity of CYP3A4 was also assessed to explore the potential mechanism underlying the interaction.ResultsThe increasing C_max (2309.67 ± 68.06 μg/L vs. 1767.67 ± 68.86 μg/L), AUC (28.84 ± 1.34 mg/L × h vs. 19.57 ± 2.76 mg/L × h), prolonged t_1/2 (9.80 ± 2.33 h vs. 6.24 ± 1.53 h), and decreased clearance rate (1.46 ± 0.26 vs. 2.42 ± 0.40) of nobilein was observed in rats. Anemarsaponin BII significantly enhanced the metabolic stability of nobiletin in rat liver microsomes (half-life increased from 31.56 min to 39.44 min) and suppressed the transport of nobiletin in Caco-2 cells (efflux rate decreased from 1.57 ± 0.04 to 1.30 ± 0.03). The inhibitory effect of anemarsaponin BII on CYP3A4 was also found with an IC₅₀ value of 10.23 μM.Discussion and conclusionsThe interaction between anemarsaponin BII and nobiletin was induced by the inhibition of CYP3A4, which should draw special attention in their clinical co-administration.     

The pharmacokinetics of darexaban are not affected to a clinically relevant degree by rifampicin,a strong inducer of P-glycoprotein and CYP3A4

AIMS

We investigated the effects of rifampicin on the pharmacokinetics (PK) of the direct clotting factor Xa inhibitor darexaban (YM150) and its main active metabolite, darexaban glucuronide (YM-222714), which almost entirely determines the antithrombotic effect.

METHODS

In this open-label, single-sequence study, 26 healthy men received one dose of darexaban 60 mg on day 1 and oral rifampicin 600 mg once daily on days 4−14. On day 11, a second dose of darexaban 60 mg was given with rifampicin. Blood and urine were collected after study drug administration on days 1−14. The maximal plasma drug concentration (C_max) and exposure [area under the plasma concentration–time curve from time zero to time of quantifiable measurable concentration; (AUC_last) or AUC_last extrapolated to infinity (AUC_∞)] were assessed by analysis of variance of PK. Limits for statistical significance of 90% confidence intervals for AUC and C_max ratios were predefined as 80−125%.

RESULTS

Darexaban glucuronide plasma exposure was not affected by rifampicin; the geometric mean ratio (90% confidence interval) of AUC_last with/without rifampicin was 1.08 (1.00, 1.16). The C_max of darexaban glucuronide increased by 54% after rifampicin [ratio 1.54 (1.37, 1.73)]. The plasma concentrations of darexaban were very low (<1% of darexaban glucuronide concentrations) with and without rifampicin. Darexaban alone or in combination with rifampicin was generally safe and well tolerated.

CONCLUSIONS

Overall, rifampicin did not affect the PK profiles of darexaban glucuronide and darexaban to a clinically relevant degree, suggesting that the potential for drug−drug interactions between darexaban and CYP3A4 or P-glycoprotein-inducing agents is low.     

Antrodia cinnamomea exerts an anti-hepatoma effect by targeting PI3K/AKT-mediated cell cycle progression in vitro and in vivo

Antrodia cinnamomea is extensively used as a traditional medicine to prevention and treatment of liver cancer. However, its comprehensive chemical fingerprint is uncertain, and the mechanisms, especially the potential therapeutic target for anti-hepatocellular carcinoma (HCC) are still unclear. Using UPLC‒Q-TOF/MS, 139 chemical components were identified in A. cinnamomea dropping pills (ACDPs). Based on these chemical components, network pharmacology demonstrated that the targets of active components were significantly enriched in the pathways in cancer, which were closely related with cell proliferation regulation. Next, HCC data was downloaded from Gene Expression Omnibus database (GEO). The Cancer Genome Atlas (TCGA) and DisGeNET were analyzed by bioinformatics, and 79 biomarkers were obtained. Furtherly, nine targets of ACDP active components were revealed, and they were significantly enriched in PI3K/AKT and cell cycle signaling pathways. The affinity between these targets and their corresponding active ingredients was predicted by molecular docking. Finally, in vivo and in vitro experiments showed that ACDPs could reduce the activity of PI3K/AKT signaling pathway and downregulate the expression of cell cycle-related proteins, contributing to the decreased growth of liver cancer. Altogether, PI3K/AKT-cell cycle appears as the significant central node in anti-liver cancer of A. Cinnamomea.     

Simultaneous evaluation of substrate‐dependent CYP3A inhibition using a CYP3A probe substrates cocktail

Cytochrome P450 (P450) 3A (CYP3A) is an enzyme responsible for the metabolism of therapeutic drugs such as midazolam, nifedipine, testosterone and triazolam. It is involved in 40% of all cases of P450‐mediated metabolism of marketed drugs. Therefore, it is important to evaluate the CYP3A‐mediated drug interaction potential of new chemical entities (NCEs). In the past, one P450 isoform‐specific probe substrate has been used at a time to evaluate the degree of inhibition of P450 isoforms by using liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). However, CYP3A enzymes have been shown to have a multi‐substrate binding site. Therefore, multiple CYP3A substrates should be used to evaluate precisely the drug interaction potential of NCEs with the enzyme CYP3A. In this study, a method of screening NCEs for their potential to inhibit by CYP3A enzyme activity was developed. It involves the employment of a CYP3A substrate cocktail (including midazolam, testosterone and nifedipine). The concentration of each CYP3A probe substrate in vitro was optimized (0.1 μm for midazolam, 2 μm for testosterone and 2 μm for nifedipine) to minimize mutual drug interactions among probe substrates. The method was validated by comparing inhibition data obtained from the incubation of CYP3A with each individual substrate with data from incubation with a cocktail of all three substrates. The CYP3A inhibition profiles from the substrate cocktail approach were similar to those from the individual substrates approach. This new method could be an effective tool for the robust and accurate screening of the CYP3A inhibition potential of NCEs in drug discovery. Copyright © 2016 John Wiley & Sons, Ltd.     

Crotamiton-loaded tea tree oil containing phospholipid-based microemulsion hydrogel for scabies treatment: in vitro,in vivo evaluation,and dermatokinetic studies

Crotamiton (CRT) is a commonly approved drug prescribed for the scabies treatment in many countries across the globe. However, poor aqueous solubility and low bioavailability, and side effects restrict its use. To avoid such issues, an appropriate carrier system is necessary which can address the aforementioned challenges for attaining enhanced biopharmaceutical attributes. The current study intends to provide a detailed account on the development and evaluation of CRT-loaded microemulsion (ME) hydrogel formulation containing tea tree oil (TTO) for improved drug delivery for scabies treatment in a safe and effective manner. Pseudo-ternary phase diagrams were constructed with TTO as the oily phase, and Cremophor^®EL was used as the surfactant in a mass ratio 2:1 with co-surfactants (mixture of phospholipid 90G and Transcutol^®P), and aqueous solution as the external phase. The optimized drug-loaded ME formulation was evaluated for skin penetration, retention, compliance, and dermatokinetics. The nonirritant behavior of the formulation was revealed by skin histopathology, which showed no changes in normal skin histology. In comparison to the conventional product, dermatokinetic experiments revealed that CRT has greater penetration and distribution in the epidermis of the mice skin. The findings imply that the proposed lipid-based ME hydrogel can aid in the resolution of CRT issues by providing a better and safer delivery option to epidermis and deeper epidermis in substantial quantities.     

Effect of lopinavir/ritonavir on the pharmacokinetics of selexipag an oral prostacyclin receptor agonist and its active metabolite in healthy subjects

Aims

This study investigated the effect of a fixed dose combination of lopinavir/ritonavir on the pharmacokinetics (PK) of selexipag and its active metabolite ACT-333679.

Methods

This was an open label, randomized, single centre, two way, crossover study. Twenty healthy male subjects were treated with a single dose of 400 µg selexipag alone and in combination with multiple doses of lopinavir/ritonavir (400/100 mg) twice daily.

Results

The results showed that lopinavir/ritonavir approximately doubled the exposure to selexipag. The area under the plasma concentration–time curve from time zero to infinity (AUC(0,∞) and the maximum plasma concentration (C_max) of selexipag were 2.2- and 2.1-fold higher, respectively, than under selexipag alone, with a 90% confidence interval (CI) of the geometric mean ratio (GMR) of 1.9, 2.7 and 1.7, 2.6, respectively. For ACT-333679, the clinically more relevant component of selexipag, systemic exposure was increased by 8% (GMR of AUC(0,∞) 1.1, 90% CI 0.9, 1.3), when lopinavir/ritonavir was co-administered with selexipag.The most frequently reported adverse event (AE) was headache. A single dose of selexipag, administered either alone or together with multiple doses of lopinavir/ritonavir, was safe and well tolerated.

Conclusions

Lopinavir/ritonavir does not affect the PK parameters of selexipag and ACT-333679 to a clinically relevant extent. Therefore, adaptation of the selexipag dose is not required when co-administered with inhibitors of the organic anion-transporting polypeptide (OATP) 1B1/ 1B3, P-glycoprotein (P-gp) and/or CYP3A4.     

Time-dependent inhibition (TDI) of CYP3A4 and CYP2C9 by noscapine potentially explains clinical noscapine–warfarin interaction

AIMS

To investigate the inhibition potential and kinetic information of noscapine to seven CYP isoforms and extrapolate in vivo noscapine-warfarin interaction magnitude from in vitro data.

METHODS

The activities of seven CYP isoforms (CYP3A4, CYP1A2, CYP2A6, CYP2E1, CYP2D6, CYP2C9, CYP2C8) in human liver microsomes were investigated following co- or preincubation with noscapine. A two-step incubation method was used to examine in vitro time-dependent inhibition (TDI) of noscapine. Reversible and TDI prediction equations were employed to extrapolate in vivo noscapine–warfarin interaction magnitude from in vitro data.

RESULTS

Among seven CYP isoforms tested, the activities of CYP3A4 and CYP2C9 were strongly inhibited with an IC₅₀ of 10.8 ± 2.5 µm and 13.3 ± 1.2 µm. Kinetic analysis showed that inhibition of CYP2C9 by noscapine was best fit to a noncompetitive type with K_i value of 8.8 µm, while inhibition of CYP3A4 by noscapine was best fit to a competitive manner with K_i value of 5.2 µm. Noscapine also exhibited TDI to CYP3A4 and CYP2C9. The inactivation parameters (K_I and k_inact) were calculated to be 9.3 µm and 0.06 min⁻¹ for CYP3A4 and 8.9 µm and 0.014 min⁻¹ for CYP2C9, respectively. The AUC of (S)-warfarin and (R)-warfarin was predicted to increase 1.5% and 1.1% using C_max or 0.5% and 0.4% using unbound C_max with reversible inhibition prediction equation, while the AUC of (S)-warfarin and (R)-warfarin was estimated to increase by 110.9% and 48.9% using C_max or 41.8% and 32.7% using unbound C_max with TDI prediction equation.

CONCLUSIONS

TDI of CYP3A4 and CYP2C9 by noscapine potentially explains clinical noscapine–warfarin interaction.     

Local anesthetic lidocaine-encapsulated polymyxin–chitosan nanoparticles delivery for wound healing: in vitro and in vivo tissue regeneration

In relieving local pains, lidocaine, one of ester-type local anesthetics, has been used. To develop the lidocaine membranes of enhanced local anesthetic effects, we have designed to establish the composition of wound dressings based on lidocaine chloride (LCH) (anesthetic drug)-loaded chitosan (CS)/polymyxin B sulfate (PMB). The LCH membranes (LCH-CS/PMB) was fabricated by the LCH oxide solutions within the CS/PMB matrix. The influences of different experimental limitations on CS/PMB membrane formations were examined. The double membrane particle sizes were evaluated by scanning electron microscopy (HR-SEM). Additionally, antibacterial efficacy was developed for gram-positive and negative microorganisms. Moreover, we examined in vivo healing of skin wounds formed in mouse models over 16 days. In contrast to the untreated wounds, rapid healing was perceived in the LCH-CS/PMB-treated wound with less damaging. These findings indicate that LCH-CS/PMB-based bandaging materials could be a potential innovative biomaterial for tissue repair and regeneration for wound healing applications in an animal model.     

Effects of oral clotrimazole troches on the pharmacokinetics of oral and intravenous midazolam

AIMS

The aim of the study was to determine the effects of oral clotrimazole troches on the pharmacokinetics of oral and intravenous midazolam in the plasma.

METHODS

We conducted a randomized, open-label, four-way crossover study in 10 healthy volunteers. Each volunteer received oral midazolam 2 mg or intravenous midazolam 0.025 mg kg⁻¹ with and without oral clotrimazole troches 10 mg taken three times daily for 5 days. Each study period was separated by 14 days. Serial blood samples were collected up to 24 h after oral midazolam and 6 h after intravenous midazolam. Plasma concentrations for midazolam and its metabolite 1-hydroxymidazolam were measured and fitted to a noncompartmental model to estimate the pharmacokinetic parameters.

RESULTS

Ten healthy volunteers aged 21–26 years provided written informed consent and were enrolled into the study. Clotrimazole decreased the apparent oral clearance of midazolam from 57 ± 13 l h⁻¹[95% confidence interval 48, 66] to 36 ± 9.8 l h⁻¹ (95% confidence interval 29, 43) (P= 0.003). These changes were accompanied by a decrease in the area under the concentration–time curve (mean difference 22 µg h⁻¹ l⁻¹, P= 0.001) and bioavailability (mean difference 0.21, P= NS). There were no significant differences in the systemic clearance of midazolam with or without clotrimazole troches.

CONCLUSIONS

Oral clotrimazole troches decreased the apparent oral clearance of midazolam; no significant differences in the systemic clearance of midazolam were found.     

Facile design of lidocaine-loaded polymeric hydrogel to persuade effects of local anesthesia drug delivery system: complete in vitro and in vivo toxicity analyses

The principal goal of the present investigation was to enterprise new and effective drug delivery vesicle for the sustained delivery of local anesthetic lidocaine hydrochloride (LDC), using a novel combination of copolymeric hydrogel with tetrahydroxyborate (COP–THB) to improve bioactivity and therapeutic potential. To support this contention, the physical and mechanical properties, rheological characteristics, and component release of candidate formulations were investigated. An optimized formulation of COP–THB containing LDC to an upper maximum concentration of 1.5% w/w was assessed for drug crystallization. The biocompatibility of the prepared COP–THB hydrogel was exhibited strong cell survival (96%) and growth compatibility on L929 fibroblast cell lines, which was confirmed by using methods of MTT assay and microscopic observations. The COP–THB hydrogel release pattern is distinct from that of COP–THB/LDC hydrogels by the slow-release rate and the low percentage of cumulative release. In vivo evaluations were demonstrated the anesthetic effects and toxicity value of treated samples by using mice models. In addition, COP–THB/LDC hydrogels significantly inhibit in vivo tumor growth in mice model and effectively reduced it is in vivo toxicity. The pharmacological evaluation showed that encapsulation of LDC in COP–THB hydrogels prolonged its anesthetic action with favorable in vitro and in vivo compatibility. This novel design may theoretically be used in promising studies involving the controlled release of local anesthetics.

Highlights

• Development a modified sustained release system for the local anesthetic lidocaine.
• PVP-THB hydrogel to improve the pharmacological properties of the drug and their anesthetic activities.
• Profiles of PVP-THB/LDC showed that the effective release of associated lidocaine.
• This new formulation could potentially be used in future local anesthetics.

     

Precise engineering of cetuximab encapsulated gadollium nanoassemblies: in vitro ultrasound diagnosis and in vivo thyroid cancer therapy

We report the formulation of nanoassemblies (NAs) comprising C225 conjugates Gd-PFH-NAs (C-Gd-PFH-NAs) for low-intensity focused ultrasound diagnosis ablation of thyroid cancer. C-Gd-PFH-NAs showed excellent stability in water, phosphate-buffered saline (PBS), and 20% rat serum. Transmission electron microscopy (TEM) images also revealed the effective construction of C-Gd-PFH-NAs as common spherical assemblies. The incubation of C625 thyroid carcinoma with C-Gd-PFH-NAs triggers apoptosis, as confirmed by flow cytometry analysis. The C-Gd-PFH-NAs exhibited antitumor efficacy in human thyroid carcinoma xenografts, where histopathological results further confirmed these outcomes. Furthermore, we were able to use low-intensity focused ultrasound diagnosis imaging (LIFUS) to examine the efficiency of C-Gd-PFH-NAs in thyroid carcinoma in vivo. These findings clearly show that the use of LIFUS agents with high performance imaging in different therapeutic settings will have extensive potential for future biomedical applications.     

D-optimal mixture design for optimization of topical dapsone niosomes: in vitro characterization and in vivo activity against Cutibacterium acnes

This study aimed to illustrate the use of D-optimal mixture design (DOMD) for optimization of an enhancer containing Dapsone niosomal formula for acne topical treatment. Mixture components (MixCs) studied were: Span 20, Cholesterol, and Cremophor RH. Different responses were measured. Optimized formula (OF) was selected to minimize particle size and maximize absolute zeta potential and entrapment efficiency. Optimized formula gel (OF-gel) was prepared and characterized. OF-gel in vivo skin penetration using confocal laser scanning microscopy and activity against Cutibacterium acnes in acne mouse model were studied. Based on DOMD results analysis, adequate models were derived. Piepel and contour plots were plotted accordingly to explain how alteration in MixCs L-pseudo values affected studied responses and regions for different responses’ values. The OF had suitable predicted responses which were in good correlation with the actually measured ones. The OF-gel showed suitable characterization and in vivo skin penetration up to the dermis layer. In vivo acne mouse-model showed that OF-gel-treated group (OF-gel-T-gp) had significantly better recovery (healing) criteria than untreated (UT-gp) and Aknemycin^®-treated (A-T-gp) groups. This was evident in significantly higher reduction of inflammation percent observed in OF-gel-T-gp than both UT-gp and A-T-gp. Better healing in OF-gel-T-gp compared with other groups was also verified by histopathological examination. Moreover, OF-gel-T-gp and A-T-gp bacterial loads were non-significantly different from each other but significantly lower than UT-gp. Thus, DOMD was an adequate statistical tool for optimization of an appropriate enhancer containing Dapsone niosomal formula that proved to be promising for topical treatment of acne.     

In vitro and in vivo evaluation of the inhibition potential of risperidone toward clozapine biotransformation

AIMS

To study the impact of risperidone (RISP) on clozapine (CLZ) biotransformation in vitro in microsomal fractions containing varying expression of CYP oxidases and in vivo in patients.

METHODS

Human liver microsomes (n= 11) were assessed for expression of CYPs 1A2, 2D6 and 3A4, because these enzymes mediate RISP and CLZ oxidation. Inhibition of CLZ oxidation by RISP was assessed. Plasma CLZ elimination was estimated in patients with schizophrenia who received either CLZ alone or the CLZ–RISP combination (n= 10 per group).

RESULTS

(i) The CYP3A4 and CYP1A2 inhibitors ketoconazole and fluvoxamine inhibited CLZ oxidation to varying extents in individual microsomal fractions. (ii) RISP did not inhibit CLZ oxidation, regardless of variations in CYP expression. (iii) RISP co-administration did not impair CLZ clearance.

CONCLUSIONS

No evidence was found for CYP-mediated inhibitory or pharmacokinetic interactions between RISP and CLZ. Occasional literature reports of such interactions may involve other pathways that participate in CLZ disposition.     

甲硝唑对兰索拉唑在大鼠体内药动学的影响

目的:研究甲硝唑在大鼠体内对兰索拉唑药动学特征的影响。方法:通过对兰索拉唑及细胞色素P450酶2C19(CYP2C19)代谢产物5-羟基兰索拉唑和细胞色素P450酶3A4(CYP3A4)代谢产物兰索拉唑砜的血药浓度的测定,计算大鼠体内药动学参数,以甲硝唑联合兰索拉唑用药组与兰索拉唑单独用药组的AUC0-4h比值为指标,研究甲硝唑对大鼠体内兰索拉唑代谢的影响。结果:联用甲硝唑后,兰索拉唑的AUC0-4h降低为单独使用兰索拉唑组的(0.20±0.06)倍(P<0.05)。甲硝唑显著增加5-羟基兰索拉唑与兰索拉唑AUC0-4h的比值,从(0.24±0.08)增至(0.39±0.19)(P<0.05)。结论:甲硝唑在大鼠体内对兰索拉唑CYP3A4主导的磺化代谢抑制作用不明显,对CYP2C19主导的羟化代谢途径可能有诱导作用。     

Metabolism-related pharmacokinetic drug?drug interactions with tyrosine kinase inhibitors: current understanding,challenges and recommendations

Drug−drug interactions (DDIs) occur when a patient''s response to the drug is modified by administration or co-exposure to another drug. The main cytochrome P450 (CYP) enzyme, CYP3A4, is implicated in the metabolism of almost all of the tyrosine kinase inhibitors (TKIs). Therefore, there is a substantial potential for interaction between TKIs and other drugs that modulate the activity of this metabolic pathway. Cancer patients are susceptible to DDIs as they receive many medications, either for supportive care or for treatment of toxicity. Differences in DDI outcomes are generally negligible because of the wide therapeutic window of common drugs. However for anticancer agents, serious clinical consequences may occur from small changes in drug metabolism and pharmacokinetics. Therefore, the objective of this review is to highlight the current understanding of DDIs among TKIs, with a focus on metabolism, as well as to identify challenges in the prediction of DDIs and provide recommendations.     

Precise engineering of hybrid molecules-loaded macromolecular nanoparticles shows in vitro and in vivo antitumor efficacy toward the treatment of nasopharyngeal cancer cells

Cancers continue to be the second leading cause of death worldwide. Despite the development and improvement of surgery, chemotherapy, and radiotherapy in cancer management, effective tumor ablation strategies are still in need due to high cancer patient mortality. Hence, we have established a new approach to achieve treatment-actuated modifications in a tumor microenvironment by using synergistic activity between two potential anticancer drugs. Dual drug delivery of gemcitabine (GEM) and cisplatin (PT) exhibits a great anticancer potential, as GEM enhances the effect of PT treatment of human cells by providing stability of the microenvironment. However, encapsulation of GEM and PT fanatical by methoxypoly(ethylene glycol)-block-poly(D, L-lactic acid) (PEG-PLA in termed as NPs) is incompetent owing to unsuitability between the binary Free GEM and PT core and the macromolecular system. Now, we display that PT can be prepared by hydrophobic coating of the dual drug centers with dioleoylphosphatidic acid (DOPA). The DOPA-covered PT can be co-encapsulated in PLGA NPs alongside GEM to stimulate excellent anticancer property. The occurrence of the PT suggestively enhanced the encapsulations of GEM into PLGA NPs (GEM-PT NPs). Further, the morphology of GEM NPs, PT NPs, and GEM-PT NPs and nanoparticle size was examined by transmission microscopy (TEM), respectively. Furthermore GEM-PT NPs induced significant apoptosis in human nasopharyngeal carcinoma CNE2 and SUNE1 cancer cells by in vitro. The morphological observation and apoptosis were confirmed by the various biochemical assays (AO-EB, nuclear staining, and annexin V-FITC). In a xenograft model of nasopharyngeal cancer, this nanotherapy shows a durable inhibition of tumor progression upon the administration of a tolerable dose. Our results suggest that a macromolecular hydrophobic and highly toxic drug can be rationally converted into a pharmacologically efficient and self-deliverable of nanotherapy.     

Artemether-lumefantrine co-administration with antiretrovirals: population pharmacokinetics and dosing implications

AIM

Drug–drug interactions between antimalarial and antiretroviral drugs may influence antimalarial treatment outcomes. The aim of this study was to investigate the potential drug–drug interactions between the antimalarial drugs, lumefantrine, artemether and their respective metabolites desbutyl-lumefantrine and dihydroartemisinin, and the HIV drugs efavirenz, nevirapine and lopinavir/ritonavir.

METHOD

Data from two clinical studies, investigating the influence of the HIV drugs efavirenz, nevirapine and lopinavir/ritonavir on the pharmacokinetics of the antimalarial drugs lumefantrine, artemether and their respective metabolites, in HIV infected patients were pooled and analyzed using a non-linear mixed effects modelling approach.

RESULTS

Efavirenz and nevirapine significantly decreased the terminal exposure to lumefantrine (decrease of 69.9% and 25.2%, respectively) while lopinavir/ritonavir substantially increased the exposure (increase of 439%). All antiretroviral drugs decreased the total exposure to dihydroartemisinin (decrease of 71.7%, 41.3% and 59.7% for efavirenz, nevirapine and ritonavir/lopinavir, respectively). Simulations suggest that a substantially increased artemether-lumefantrine dose is required to achieve equivalent exposures when co-administered with efavirenz (250% increase) and nevirapine (75% increase). When co-administered with lopinavir/ritonavir it is unclear if the increased lumefantrine exposure compensates adequately for the reduced dihydroartemisinin exposure and thus whether dose adjustment is required.

CONCLUSION

There are substantial drug interactions between artemether-lumefantrine and efavirenz, nevirapine and ritonavir/lopinavir. Given the readily saturable absorption of lumefantrine, the dose adjustments predicted to be necessary will need to be evaluated prospectively in malaria-HIV co-infected patients.     

Effect of diammonium glycyrrhizinate on pharmacokinetics of omeprazole by regulating cytochrome P450 enzymes and plasma protein binding rate

1. In clinical practice, diammonium glycyrrhizinate is usually used with omeprazole in patients with viral hepatitis and cirrhosis accompanied by peptic ulcers. However, the drug interaction between diammonium glycyrrhizinate and omeprazole remains unclear.

2. In this study, the effects of diammonium glycyrrhizinate on the pharmacokinetics of omeprazole was investigated by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytical method. Male Sprague–Dawley rats were randomly assigned to two groups: omeprazole and omeprazole?+?diammonium glycyrrhizinate, and the main pharmacokinetic parameters were estimated after oral administration. It was found that using the omeprazole along with the diammonium glycyrrhizinate increased the AUC, AUMC, C_max for omeprazole.

3. For this reason, we used the LC-MS/MS to detect the binding rate of plasma protein (BRPP) of omeprazole in rats, it was found that diammonium glycyrrhizinate could decrease the BRPP in rats. In addition, we found that diammonium glycyrrhizinate specifically inhibited the enzyme activity of the CYP2C19 and CYP3A4, which are involved in the metabolism of the omeprazole.

4. These results mean that diammonium glycyrrhizinate could inhibit the metabolism and increase the plasma concentration of the omeprazole in rats. Overall, diammonium glycyrrhizinate can influence the pharmacokinetics of omeprazole by inhibiting CYP2C19 and CYP3A4 activities and decreasing BRPP of omeprazole.     

Assessment of cytochrome P450‐mediated drug–drug interaction potential of orteronel and exposure changes in patients with renal impairment using physiologically based pharmacokinetic modeling and simulation

Orteronel is a nonsteroidal, selective inhibitor of 17,20‐lyase that was recently in phase 3 clinical development as a treatment for castration‐resistant prostate cancer. In humans, the primary clearance route for orteronel is renal excretion. Human liver microsomal studies indicated that orteronel weakly inhibits CYP1A2, 2C8, 2C9 and 2C19, with IC₅₀ values of 17.8, 27.7, 30.8 and 38.8 µm , respectively, whereas orteronel does not inhibit CYP2B6, 2D6 or 3A4/5 (IC₅₀ > 100 µm ). Orteronel also does not exhibit time‐dependent inhibition of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A4/5. The results of a static model indicated an [I]/K_i ratio >0.1 for CYP1A2, 2C8, 2C9 and 2C19. Therefore, a physiologically based pharmacokinetic (PBPK) model was developed to assess the potential for drug–drug interactions (DDIs) between orteronel and theophylline, repaglinide, (S)‐warfarin and omeprazole, which are sensitive substrates of CYP1A2, 2C8, 2C9 and 2C19, respectively. Simulation of the area under the plasma concentration–time curve (AUC) of these four CYP substrates in the presence and absence of orteronel revealed geometric mean AUC ratios <1.25. Therefore, in accordance with the 2012 US FDA Draft Guidance on DDIs, orteronel can be labeled a ‘non‐inhibitor’ and further clinical DDI evaluation is not required. In PBPK models of moderate and severe renal impairment, the AUC of orteronel was predicted to increase by 52% and 83%, respectively. These results are in agreement with those of a clinical trial in which AUC increases of 38% and 87% were observed in patients with moderate and severe renal impairment, respectively. Copyright © 2014 John Wiley & Sons, Ltd.