In Vitro-In Vivo Predictive Dissolution-Permeation-Absorption Dynamics of Highly Permeable Drug Extended-Release Tablets via Drug Dissolution/Absorption Simulating System and pH Alteration.

Each of dissolution and permeation may be a rate-limiting factor in the absorption of oral drug delivery. But the current dissolution test rarely took into consideration of the permeation property. Drug dissolution/absorption simulating system (DDASS) valuably gave an insight into the combination of drug dissolution and permeation processes happening in human gastrointestinal tract. The simulated gastric/intestinal fluid of DDASS was improved in this study to realize the influence of dynamic pH change on the complete oral dosage form. To assess the effectiveness of DDASS, six high-permeability drugs were chosen as model drugs, including theophylline (pKa1 = 3.50, pKa2 = 8.60), diclofenac (pKa = 4.15), isosorbide 5-mononitrate (pKa = 7.00), sinomenine (pKa = 7.98), alfuzosin (pKa = 8.13), and metoprolol (pKa = 9.70). A general elution and permeation relationship of their commercially available extended-release tablets was assessed as well as the relationship between the cumulative permeation and the apparent permeability. The correlations between DDASS elution and USP apparatus 2 (USP2) dissolution and also between DDASS permeation and beagle dog absorption were developed to estimate the predictability of DDASS. As a result, the common elution-dissolution relationship was established regardless of some variance in the characteristic behavior between DDASS and USP2 for drugs dependent on the pH for dissolution. Level A in vitro-in vivo correlation between DDASS permeation and dog absorption was developed for drugs with different pKa. The improved DDASS will be a promising tool to provide a screening method on the predictive dissolution-permeation-absorption dynamics of solid drug dosage forms in the early-phase formulation development.

Pharmacokinetic and Toxicological Characteristics of Tripterigium Glycosides and Their Derivatives.

BACKGROUND: Tripterigium wilfordii glycosides (TWG) demonstrate paramount bioactive effectiveness in the management of many autoimmune diseases. However, its side effects on the hepatic, nephrotic, reproductive, and cardiovascular systems have limited its immense therapeutic potentials. Triptolide (TP) and Celastrol (CL), the leading bioactive as well as toxic constituents of TWG, have been widely studied. This review aims to summarize the key mechanisms that TWG trigger the toxic reactions and the precautionary measures that could prevent and reduce such reactions. METHOD: We undertook a systemic search of bibliographic databases for peer-reviewed research literature about the toxic mechanisms and pharmacokinetic profiles of TWG. The key points of screened papers were described and combined together to make up whole. RESULTS: Totally 125 papers were referred in this paper, the majority were from Chinese academic associations. It has been reported that reactive oxygen species generation, mitochondrial respiratory chain inhibition, and metabolizing enzyme inhibition are the leading factors of the toxic reactions. The bioactive effects and toxicities of TWG are closely related to its metabolic profiles. It has been confirmed that TP and CL inhibit CYP450 and the transporters. This paper reviews and summarizes the pharmacokinetic parameters of TWG. Antioxidants, polymeric micelle and topical nanoparticle formulations have exhibited potentials in toxicity circumvention. CONCLUSION: A thorough understanding of the pharmacokinetic and toxicological characteristics of TWG combined with further in-depth study will enhance the efficacy and safety in using TWG, which would augment and improve its clinical application in the future.

Cytochrome P450 and P-Glycoprotein-Mediated Interactions Involving African Herbs Indicated for Common Noncommunicable Diseases.

Herbal remedies are regularly used to complement conventional therapies in the treatment of various illnesses in Africa. This may be because they are relatively cheap and easily accessible and are believed by many to be safe, cause fewer side effects, and are less likely to cause dependency. On the contrary, many herbs have been shown to alter the pharmacokinetics of coadministered allopathic medicines and can either synergize or antagonize therapeutic effects as well as altering the toxicity profiles of these drugs. Current disease burden data point towards epidemiological transitions characterised by increasing urbanization and changing lifestyles, risk factors for chronic diseases like hypertension, diabetes, and cancer which often present as multimorbidities. As a result, we highlight African herb-drug interactions (HDIs) modulated via cytochrome P450 enzyme family (CYP) and P-glycoprotein (P-gp) and the consequences thereof in relation to antihypertensive, antidiabetic, and anticancer drugs. CYPs are enzymes which account for to up to 70% of drug metabolism while P-gp is an efflux pump that extrudes drug substrates out of cells. Consequently, regulation of the relative activity of both CYP and P-gp by African herbs influences the effective drug concentration at the site of action and modifies therapeutic outcomes.

Targeting BNIP3 in inflammation-mediated heart failure: a novel concept in heart failure therapy.

Myocardial injury activates inflammatory mediators and provokes the integration of BCL-2/adenovirus E1B 19KD interacting protein 3 (BNIP3) into mitochondrial membranes. Translocation of BNIP3 to mitochondria inexorably causes mitochondrial fragmentation. Heart failure (HF) epitomizes the life-threatening phase of BNIP3-induced mitochondrial dysfunction and cardiomyocyte death. Available data suggest that inflammatory mediators play a key role in cardiac cell demise and have been implicated in the pathogenesis of HF syndrome. In the present study, we reviewed the changes in BNIP3 protein expression levels during inflammatory response and postulated its role in inflammation-mediated HF. We also identified inflammatory mediators' response such as stimulation of TNF-α and NO as potent inducer of BNIP3. Previous studies suggest that the pro-apoptotic protein has a common regulator with IL-1ß and induces IL-6-stimulated cardiac hypertrophy. These findings corroborate our contention that interventions designed to functionally modulate BNIP3 activity during inflammatory-mediated HF may prove beneficial in preventing HF. Such a revelation will open new avenue for further research to unravel a novel therapeutic strategy in HF diseases. Moreover, understanding of the relationship between BNIP3 and inflammatory mediators in HF pathologies will not only contribute to the discovery of drugs that can inhibit inflammation-mediated heart diseases, but also enhance the current knowledge on the key role BNIP3 plays during inflammation.