Current Drug Metabolism - Volume 21, Issue 5, 2020

Background: Exosomes are extracellular vesicles (EVs) released from cells upon fusion of an intermediate endocytic compartment with the plasma membrane. They refer to the intraluminal vesicles released from the fusion of multivesicular bodies with the plasma membrane. The contents and number of exosomes are related to diseases such as metabolic diseases, cancer and inflammatory diseases. Exosomes have been used in neurological research as a drug delivery tool and also as biomarkers for diseases. Recently, exosomes were observed in the seminal plasma of the one who is asthenozoospermia, which can affect sperm motility and capacitation. Objective: The main objective of this review is to deeply discuss the role of exosomes in spermatozoa after leaving the seminiferous tubule. Methods: We conducted an extensive search of the literature available on relationships between exosomes and exosomes in spermatozoa on the bibliographic database. Conclusion: This review thoroughly discussed the role that exosomes play in the exchange of spermatozoa after leaving the seminiferous tubule and its potential as a drug delivery tool and biomarkers for diseases as well.

Background: Exosomes play an important role in transferring information among different cell types, as they transport materials from the cell membrane to the cytoplasm. They are involved not only in normal physiological functions, but also in the occurrence and development of a variety of diseases. Cancer is a major health problem affecting humans. Currently, exosomes are considered novel stars in tumor therapy. Objective: To present a review focusing on the role of exosomes in tumorigenesis and development and the possibility of treating tumors with exosome-targeted therapies or using exosomes as carriers. Methods: We reviewed literature related to the biological origin and function of exosomes and exosome-tumor relationship. Results: Exosomes are closely related to tumor immunity, angiogenesis, pre-metastasis microenvironment, chemoresistance, energy metabolism, etc. Tumor therapy involving the targeting of exosomes involves block the generation, secretion, uptake of exosomes, and elimination of circulating exosomes, and develop antitumor vaccines. Exosome as delivery vehicles can be loaded with chemotherapeutic drugs, therapeutic genes, and other therapeutic drugs to target cells. Prospects and challenges of exosome-based tumor therapy are also discussed. Conclusion: Exosomes are involved in multiple processes during tumor development and should be further studied as novel targets for cancer therapy.

Preeclampsia is a serious pregnancy-specific disease that affects about 5%-8% of pregnant women and is the main reason for the increase in maternal and perinatal mortality. Due to unknown etiology, preeclampsia is still the main cause of increased mortality in maternal and perinatal infants, which is mainly manifested by new hypertension after 20 weeks of pregnancy. As the pathogenesis has not been fully elucidated, early diagnosis and full treatment are lacking. Exosomes secreted from the placenta to the peripheral circulation may be involved in the pathogenesis of preeclampsia and can be detected from the plasma of pregnant women after 6 weeks of pregnancy. Related studies have shown that the levels of exosomes in preeclampsia have changed, and the protein and miRNA expression profiles are also different. Therefore, monitoring changes in plasma exosomes and expression profiles may provide new ideas and new perspectives for the prediction, diagnosis and treatment of preeclampsia.

Background: Surufatinib is a potent small-molecule tyrosine kinase inhibitor and exhibited significant efficacy in the treatment of neuroendocrine tumors in clinical trials. Objective: The absorption, metabolism and excretion of surufatinib were investigated in rats and human volunteers following a single oral dose of [14C] surufatinib. Methods: The radioactivity was measured in plasma, urine, feces and bile by liquid scintillation counting, and the metabolites were characterized by liquid chromatography coupled to mass spectrometry. Results: Surufatinib was orally absorbed similarly in rats and human volunteers, with the median Tmax of 4 hours post-dose. The estimated t1/2 appeared longer in humans than in rats (mean t1/2: 3.12 hour for male rats, 6.48 hours for female rats and 23.3 hours for male human volunteers). The excretion of surufatinib was almost complete in rats and human volunteers in the studies, with the total radioactivity recovery of >90% of the dose. Similarly, in rats and humans, fecal excretion predominated (approximately 87% of the dose recovered in feces and only 5% in urine). The parent drug was the major radioactive component detected in the plasma extracts of rats and humans, and no single circulating metabolite accounted for >10% of the total radioactivity. Unchanged drug was a minor radioactive component in the excreta of rats and humans. Conclusion: Fecal excretion was the predominant way for the elimination of surufatinib and its metabolites in rats and humans. No disproportionate circulating metabolite was observed in humans.

Background: Drug-metabolizing enzymes and transporters play key roles in drug disposition and drug interactions. The alterations of their expression will influence drug pharmacokinetics and pharmacodynamics. However, the changes in the expression of enzymes and transporters in the disease state are still unclear. Objective: Our study was to investigate the changes in the expression of main enzymes and drug transporters distributed in Adriamycin nephropathy rat liver, kidney, and intestine. Methods: An intravenous injection with a single dose of Adriamycin (6mg/kg) was made to establish Adriamycin nephropathy (AN) model and normal groups were injected with normal saline. Serum was collected for lipid metabolism, renal, and hepatic function measurement. The real-time PCR and western blot were applied to determine the mRNA and protein expression of drug enzymes and transporters. Results: In the kidney, a greater expression of Mdr1, Mrp2, Mrp4 Oat2 and Oct2 mRNA was found in AN rats as compared with control rats. In the liver, the expression of Bcrp mRNA was more doubled or tripled than control groups and downregulation of Mdr1, Mrp2, Mrp4 and Bsep gene expression was found in AN rats. Besides, we observed a downward trend of Cyp1a2, Cyp3a4 and Cyp2c9 mRNA levels in AN groups. In the duodenum, the expression of Mdr1 and Mrp3 mRNA level was decreased, while Bcrp and Mrp2 mRNA were increased. Conclusion: The changes in drug-metabolizing enzymes and transporters expression in AN rats were clarified, which may be beneficial for understanding the altered pharmacokinetics and pharmacodynamics of clinical drugs and reduce unexpected clinical findings for nephropathy patients.

Background: This study aimed to reduce the amount of sulfobutylether-β-cyclodextrin (SBECD) used in the marketed voriconazole injections to meet the clinical needs of patients with moderate-to-severe renal impairment (creatinine clearance rate <50 mL/min). Objective: This study found that the surfactant Kolliphor® HS 15 (HS 15) and SBECD had significant synergistic effects on solubilizing voriconazole, and a novel voriconazole complex delivery system (VRC-CD/HS 15) was established. Methods: The complex system was characterized, and its antifungal activity was studied by dynamic light scattering, dialysis bag method, disk diffusion, and broth microdilution. Results: Compared with the control, its encapsulation efficiency (90.07±0.48%), drug loading (7.37±0.25%) and zeta potential (-4.36±1.37 mV) were increased by 1.54%, 41.19%, and 296.36%, respectively; its average particle size (13.92±0.00 nm) was reduced by 15.69%, so the complex system had better stability. Simultaneously, its drug release behavior was similar to that of the control, and it was a first-order kinetic model. Antifungal studies indicated that the complex system had noticeable antifungal effects. With the increase of drug concentration, the inhibition zone increased. The minimum inhibitory concentrations of the complex system against Cryptococcus neoformans, Aspergillus niger and Candida albicans were 0.0313 μg/mL, 1 μg/mL and 128 μg/mL, respectively. Conclusion: It showed a significant inhibitory effect on C. neoformans and had a visible therapeutic effect on Kunming mice infected with C. neoformans. Consequently, VRC-CD/HS 15 had better physicochemical properties and still had an apparent antifungal effect, and was promising as a potential alternative drug for clinical application.

Background: Despite recent therapeutic advances, osteoarthritis continues to be a challenging health problem, especially in the elderly population. Opioids, which are potent analgesics, have shown an extraordinary ability to reduce intense pain in many osteoarthritic clinical trials; however, there is an increased need for a study to integrate the reported outcomes and utilize them to achieve a better understanding. Herein, efficacy and safety aspects of opioids used to manage osteoarthritic pain were assessed and compared using a model-based meta-analysis (MBMA). Methods: To perform the analysis, a comprehensive database consisting of pain relief compounds with information on summary-level of efficacy over time, adverse events and dropout rates was compiled from multiple sources. MBMA was conducted using a nonlinear mixed-effects modeling approach. Results: The results of primary efficacy endpoint analysis indicated that the doses of oxycodone, oxymorphone, and tramadol required to produce 50% of the maximum effect were 47, 84, and 247 mg per day, respectively. Efficacytime course analysis showed that opioids had rapid time to efficacy onset, suggesting potentially powerful painrelieving effects. It was also found that gastrointestinal adverse events were the most opioid-associated and dosedependent adverse effects. In addition, the analysis revealed that opioids were well-tolerated at low to moderate doses. Conclusion: This MBMA provides clinically meaningful insights into the efficacy and safety profiles of oxycodone, oxymorphone, and tramadol. Resultantly, the presented framework analysis can have an impact in the clinic on drug development where it can guide: the optimization of doses of opioids required to manage osteoarthritic pain; the making of precise key decisions for the positioning of new drugs, and; the design of more efficient trials.