Meiyu Wang

Targeting the Phosphatidylinositol 3-Kinase/AKT Pathway for the Treatment of Multiple Myeloma

Multiple myeloma is the second most hematological malignancy, accounting for more than 10% of all blood cancers and 2% of annual cancer-related deaths due to lack of curable drugs. Novel and molecularly targeted anti-MM drugs are in urgent need. The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway plays a critical regulatory role in multiple myeloma pathophysiology, including survival, proliferation, migration, angiogenesis, as well as drug resistance, and has emerged as a key therapeutic target. Many potent inhibitors targeting this pathway have been developed and some have been moved for clinical evaluations for multiple myeloma. In this review, we highlighted the role of the PI3K/AKT pathway in the pathogenesis of multiple myeloma, and current advances in drug discovery for this class of inhibitors. Discovery strategies toward the PI3K/AKT inhibitors were also discussed.

Pathway-Dependent Inhibition of Paclitaxel Hydroxylation by Kinase Inhibitors and Assessment of Drug–Drug Interaction Potentials

Paclitaxel is often used in combination with small molecule kinase inhibitors to enhance antitumor efficacy against various malignancies. Because paclitaxel is metabolized by CYP2C8 and CYP3A4, the possibility of drug–drug interactions mediated by enzyme inhibition may exist between the combining agents. In the present study, a total of 12 kinase inhibitors were evaluated for inhibitory potency in human liver microsomes by monitoring the formation of CYP2C8 and CYP3A4 metabolites simultaneously. For reversible inhibition, nilotinib was found to be the most potent inhibitor against both CYP2C8 and CYP3A4, and the inhibition potency could be explained by strong hydrogen binding based on molecular docking simulations and type II binding based on spectral analysis. Comparison of Ki values revealed that the CYP2C8 pathway was more sensitive toward some kinase inhibitors (such as axitinib), while the CYP3A4 pathway was preferentially inhibited by others (such as bosutinib). Pathway-dependent inactivation (time-dependent inhibition) was also observed for a number of kinase inhibitors against CYP3A4 but not CYP2C8. Further studies showed that axitinib had a KI of 0.93 μM and kinact of 0.0137 min−1, and the observed inactivation toward CYP3A4 was probably due to the formation of reactive intermediate(s). Using a static model, a reasonably accurate prediction of drug–drug interactions was achieved by incorporating parallel pathways and hepatic extraction ratio. The present results suggest that potent and pathway-dependent inhibition of CYP2C8 and/or CYP3A4 pathways by kinase inhibitors may alter the ratio of paclitaxel metabolites in vivo, and that such changes can be clinically relevant as differential metabolism has been linked to paclitaxel-induced neurotoxicity in cancer patients.

Steviol glucuronidation and its potential interaction with UDP-glucuronosyltransferase 2B7 substrates

Hydrolysis of stevioside and rebaudioside A in the gastrointestinal tract after oral intake leads to the formation of steviol, the aglycone, which is absorbed into the circulation. Although in vivo studies have shown that steviol is cleared from the body via glucuronidation, the role of liver vs. intestine in steviol glucuronidation has not been well defined and related UDP-glucuronosyltransferases (UGTs) have not been identified. The present study investigated steviol glucuronidation and obtained kinetic parameters in liver and intestinal microsomes of human and rat, as well as in recombinant human UGT systems. Results suggest that organ specificity exists in the intrinsic clearance of the glucuronidation reaction. Steviol glucuronidation was primarily mediated by UGT2B7 at low concentration and UGT2B7 and UGT1A3 at high concentration. Inhibition studies with selected UGT2B7 substrates indicate that diclofenac displayed a relatively strong inhibition (Ki, 4.2 μM) against steviol glucuronidation in human liver microsomes. Taken together, the identification of the involvement of UGT2B7 in steviol glucuronidation would provide a mechanistic basis for the evaluation of the interaction between steviol and diclofenac. As metabolic clearance of botanical-derived products can be the objects (victims) of botanical-drug interactions, further studies are needed to investigate the in vivo relevance of such interactions.

LC-MS/MS method for the simultaneous quantitation of three active components derived from a novel prodrug against schistosome infection.

Schistosomiasis is an infectious disease that has been recognized as a severe health burden for some regions of the world. While praziquantel is the drug of choice, there is an unmet medical need for novel therapies with greater efficacy and resistant profile. DW-3-15 is a novel and promising prodrug possessing both adult and juvenile schistosomes killing capability. Its proposed hydrolytic products, artesunate (ARS), dihydroartemisinin (DHA) and 10-hydroxypraziquantel (10-OHPZQ), are all active in preventing schistosomal infection in relevant disease models. To support pharmacokinetic and PK-PD studies of DW-3-15, a simple, specific and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous determination of the three active components in rat plasma. Using a short C18 column (2.1 mm × 50 mm, 5 μm) with linear gradient, a baseline resolution of the three analytes and corresponding internal standards was achieved with a total run time of 6 min. Mass detection was carried out by electrospray ionization in positive MRM mode with ion transitions of m/z 402.2→m/z 267.3 for ARS, m/z 302.2→m/z 163.1 for DHA, and m/z 329.2→m/z 219.4 for 10-OHPZQ. The method was linear over concentration ranges of 1.0-500 ng/mL for ARS, 5.0-2500 ng/mL for DHA, and 1.0-500 ng/mL for 10-OHPZQ. The accuracy was within ±10.0% for ARS, ±6.4% for DHA, and ±13.0% for 10-OHPZQ. The within-run and between-run precision of all three analytes at four concentrations tested were less than 15%, except at the LLOQ for DHA which was between 15 and 20%. The method was successfully applied to pharmacokinetic evaluation of DW-3-15 in rats following intravenous administration.

Abcb1a but not Abcg2 played a predominant role in limiting the brain distribution of Huperzine A in mice

Huperzine A has been used for improving symptoms of Alzheimers disease. Its cholinergic side effect is thought to be an exaggerated pharmacological outcome linked to its high brain or CNS concentrations. Although Huperzine A is brain penetrable, its interaction with efflux transporters (ABCB1 and ABCG2) has not been fully investigated. The aim of the present study was to characterize roles of ABCB1 and ABCG2 in the transmembrane transport of Huperzine A and identify a rate limiting step in its brain distribution. Data obtained from stably transfected MDCK II cells showed that Huperzine A is a substrate of ABCB1 but not ABCG2. ABCB1 inhibitors significantly inhibited ABCB1 mediated efflux of Huperzine A. In Abcb1a-/- mice, the brain to plasma concentration ratio of Huperzine A was significantly increased as compared to the wild type mice, while there were no obvious differences between the wild type and Abcg2-/- mice. Taken together, the present study demonstrated that ABCB1 but not ABCG2 played a predominant role in the efflux of Huperzine A across BBB. The current finding is clinically relevant as changes in ABCB1 activity in the presence of ABCB1 inhibitors or genetic polymorphism may affect efficacy and safety of Huperzine A.