Jaime A. Yáñez

Pharmacometrics of Stilbenes: Seguing Towards the Clinic

Stilbenes are small molecular weight (approximately 200-300 g/mol), naturally occurring compounds and are found in a wide range of plant sources, aromatherapy products, and dietary supplements. These molecules are synthesized via the phenylpropanoid pathway and share some structural similarities to estrogen. Upon environmental threat, the plant host activates the phenylpropanoid pathway and stilbene structures are produced and subsequently secreted. Stilbenes act as natural protective agents to defend the plant against viral and microbial attack, excessive ultraviolet exposure, and disease. One stilbene, resveratrol, has been extensively studied and has been shown to possess potent anti-cancer, antiinflammatory and anti-oxidant activities. Found primarily in the skins of grapes, resveratrol is synthesized by Vitis vinifera grapevines in response to fungal infection or other environmental stressors. Considerable research showing resveratrol to be an attractive candidate in combating a wide variety of cancers and diseases has fueled interest in determining the disease-fighting capabilities of other structurally similar stilbene compounds. The purpose of this review is to describe four such structurally similar stilbene compounds, piceatannol, pinosylvin, rhapontigenin, and pterostilbene and detail some current pharmaceutical research and highlight their potential clinical applications.

Clinical toxicities of nanocarrier systems.

Toxicity of nanocarrier systems involves physiological, physicochemical, and molecular considerations. Nanoparticle exposures through the skin, the respiratory tract, the gastrointestinal tract and the lymphatics have been described. Nanocarrier systems may induce cytotoxicity and/or genotoxicity, whereas their antigenicity is still not well understood. Nanocarrier may alter the physicochemical properties of xenobiotics resulting in pharmaceutical changes in stability, solubility, and pharmacokinetic disposition. In particular, nanocarriers may reduce toxicity of hydrophobic cancer drugs that are solubilized. Nano regulation is still undergoing major changes to encompass environmental, health, and safety issues. The rapid commercialization of nanotechnology requires thoughtful environmental, health and safety research, meaningful, and an open discussion of broader societal impacts, and urgent toxicological oversight action.

Intestinal lymphatic transport for drug delivery

Abstract Intestinal lymphatic transport has been shown to be an absorptive pathway following oral administration of lipids and an increasing number of lipophilic drugs, which once absorbed, diffuse across the intestinal enterocyte and while in transit associate with secretable enterocyte lipoproteins. The chylomicron-associated drug is then secreted from the enterocyte into the lymphatic circulation, rather than the portal circulation, thus avoiding the metabolically-active liver, but still ultimately returning to the systemic circulation. Because of this parallel and potentially alternative absorptive pathway, first-pass metabolism can be reduced while increasing lymphatic drug exposure, which opens the potential for novel therapeutic modalities and allows the implementation of lipid-based drug delivery systems. This review discusses the physiological features of the lymphatics, enterocyte uptake and metabolism, links between drug transport and lipid digestion/re-acylation, experimental model (in vivo, in vitro, and in silico) of lymphatic transport, and the design of lipid- or prodrug-based drug delivery systems for enhancing lymphatic drug transport.

Flip-flop pharmacokinetics - delivering a reversal of disposition: challenges and opportunities during drug development

Flip-flop pharmacokinetics is a phenomenon often encountered with extravascularly administered drugs. Occurrence of flip-flop spans preclinical to human studies. The purpose of this article is to analyze both the pharmacokinetic interpretation errors and opportunities underlying the presence of flip-flop pharmacokinetics during drug development. Flip-flop occurs when the rate of absorption is slower than the rate of elimination. If it is not recognized, it can create difficulties in the acquisition and interpretation of pharmacokinetic parameters. When flip-flop is expected or discovered, a longer duration of sampling may be necessary in order to avoid overestimation of fraction of dose absorbed. Common culprits of flip-flop disposition are modified dosage formulations; however, formulation characteristics such as the drug chemical entities themselves or the incorporated excipients can also cause the phenomenon. Yet another contributing factor is the physiological makeup of the extravascular site of administration. In this article, these causes of flip-flop pharmacokinetics are discussed with incorporation of relevant examples and the implications for drug development outlined.

Multiple peaking phenomena in pharmacokinetic disposition.

Abstractmultiple peaking in the blood fluid concentration-time curve is a phenomenon occasionally encountered in pharmacokinetics. When it occurs, it can create difficulties in the determination and interpretation of pharmacokinetic parameters. Multiple peaking can occur as a consequence of a number of different mechanisms. These include, in addition to others, factors related to the formulation, be it the drug chemical entity itself or other formulation-related factors such as the excipients incorporated into the product design. Another contributing factor that can work in concert with the formulation is the physiological makeup of the gastrointestinal tract itself. This includes the pH and components of bile such as bile salts and phospholipids, the secretion of which is regulated by hormonal and dietary factors. In some cases, biochemical differences in the regional areas of the gastrointestinal tract, such as regiospecificity in bile concentrations and/or transport proteins, could contribute to windows for absorption that result in multiple peaking of xenobiotics. One of the most common sources of multiple peaking is contributed by biliary secretion followed by intestinal reabsorption of a drug, a process for which the term ‘enterohepatic recycling’ has been coined. This cause of multiple peaking is associated with special consideration in the calculation and interpretation of the drug clearance and volume of distribution. In this review, each of these various causes of multiple peaking is discussed, with incorporation of relevant examples for illustrative purposes.

Pharmacokinetics of selected stilbenes: rhapontigenin, piceatannol and pinosylvin in rats.

The pharmacokinetics of piceatannol, pinosylvin and rhapontigenin were characterized in male Sprague‐Dawley rats after single intravenous doses of 10 mg kg−1 of each stilbene. Serial blood samples were collected via a catheter inserted into the right jugular vein and plasma samples were analysed for the selected stilbenes concentrations using reverse phase HPLC methods. After an acute intravenous dose of piceatannol, plasma AUC, urine t½, CL and Vd were 8.48 ± 2.48 μgh mL−1, 19.88 ± 5.66 h, 2.13 ± 0.92 Lh−1 kg−1 and 10.76 ± 2.88 Lkg−1 (mean ± s.e.m.), respectively. The acute intravenous dose of pinosylvin yielded the plasma AUC, urine t ½, CL and Vd values of 5.23 ± 1.20 μgh mL−1, 13.13 ± 2.05 h, 1.84 ± 0.44 Lh−1 kg−1 and 2.29 ± 0.56 Lkg−1 (mean ± s.e.m.), respectively. Rhapontigenin intravenous dosing yielded the plasma AUC, urine t½, CL and Vd values of 8.39 ±0.10 μgh mL−1, 25.31 ± 1.46 h, 1.18 ± 0.035 Lh−1 kg−1 and 11.05 ± 0.17 Lkg−1 (mean ± s.e.m.), respectively. Each stilbene was extensively glucuronidated. These stilbenes were predominantly eliminated via non‐urinary routes. All three stilbenes were highly distributed into tissues and were highly extracted by the liver. The detectable plasma half‐lives of these xenobiotics appear to be relatively short. However, utilizing urinary concentration‐time data, much longer elimination half‐lives were evident. The estimates of oral bioavailability characterize these stilbenes as poorly bioavailable compounds.

Effect of dehydration on raspberries: polyphenol and anthocyanin retention, antioxidant capacity, and antiadipogenic activity.

Fresh and dried raspberries prepared by freeze drying (FD), microwave-vacuum (MIVAC), hot-air drying (HAD), and a combination of hot-air drying and microwave-vacuum (HAD/MIVAC) drying methods were evaluated for polyphenol retention, total polyphenol and anthocyanin contents, total antioxidant capacity, and antiadipogenic activity (the inhibition of fat cell development). Ellagic acid and quercetin were present in the largest concentrations in fresh and dehydrated raspberries. Dehydration led to a loss of polyphenols and anthocyanins and antioxidant capacity. Polyphenols (aglycone form) were retained in the greatest amount: 20% (freeze dried) to 30% (HAD/MIVAC) (fresh = 100%). A total of 30% of polyphenols (glycoside form) were retained in raspberries dried by the HAD/MIVAC methods with 5% of retention observed for raspberries dried by FD, HAD, or MIVAC. FD and MIVAC resulted in higher retention of anthocyanins (aglycone form) than other drying methods. It was also observed that antioxidant activity was reduced by dehydration. Adipogenesis was inhibited by polyphenolic glycosides (30%) and aglycones (30% to 40%) in fresh and HAD/MIVAC raspberries. Extracts from dried raspberries by HAD/MIVAC methods were relatively more effective at inhibiting adipogenesis compared to HAD and FD dried raspberries.

Improving Nutritional Value of Dried Blueberries (Vaccinium corymbosum L.) Combining Microwave-Vacuum, Hot-Air Drying and Freeze Drying Technologies

Blueberries (Vaccinium corymbosum L.) were dried combining microwave-vacuum, hot-air drying and freeze drying technologies to retain their nutritional value. Polyphenol retention, total polyphenols, anthocyanins, and antioxidant activity were evaluated in dried blueberries. Glycoside compounds for ellagic acid, quercetin, and kaempferol exhibited a higher retention than phloridzin, and R- and S-naringin in dried blueberries following dehydration. Freeze and HA-MIVAC® dried blueberries had a higher retention of total polyphenols and anthocyanins. Freeze dried blueberries had higher antioxidant activity, followed by the combination of HA-MIVAC®, MIVAC® and HA drying methods. FD, HA-MIVAC® and MIVAC® treated blueberries had a higher retention of individual polyphenols than HA treated blueberries, indicating that the nutritional properties of berries may be retained to a greater extent when these processes are employed.

Understanding the Hysteresis Loop Conundrum in Pharmacokinetic /Pharmacodynamic Relationships

Hysteresis loops are phenomena that sometimes are encountered in the analysis of pharmacokinetic and pharmacodynamic relationships spanning from pre-clinical to clinical studies. When hysteresis occurs it provides insight into the complexity of drug action and disposition that can be encountered. Hysteresis loops suggest that the relationship between drug concentration and the effect being measured is not a simple direct relationship, but may have an inherent time delay and disequilibrium, which may be the result of metabolites, the consequence of changes in pharmacodynamics or the use of a non-specific assay or may involve an indirect relationship. Counter-clockwise hysteresis has been generally defined as the process in which effect can increase with time for a given drug concentration, while in the case of clockwise hysteresis the measured effect decreases with time for a given drug concentration. Hysteresis loops can occur as a consequence of a number of different pharmacokinetic and pharmacodynamic mechanisms including tolerance, distributional delay, feedback regulation, input and output rate changes, agonistic or antagonistic active metabolites, uptake into active site, slow receptor kinetics, delayed or modified activity, time-dependent protein binding and the use of racemic drugs among other factors. In this review, each of these various causes of hysteresis loops are discussed, with incorporation of relevant examples of drugs demonstrating these relationships for illustrative purposes. Furthermore, the effect that pharmaceutical formulation has on the occurrence and potential change in direction of the hysteresis loop, and the major pharmacokinetic / pharmacodynamic modeling approaches utilized to collapse and model hysteresis are detailed.

A Cremophor-Free Formulation for Tanespimycin (17-AAG) Using PEO-b-PDLLA Micelles: Characterization and Pharmacokinetics in Rats

Tanespimycin (17-allylamino-17-demethoxygeldanamycin or 17-AAG) is a promising heat shock protein 90 inhibitor currently undergoing clinical trials for the treatment of cancer. Despite its selective mechanism of action on cancer cells, 17-AAG faces challenging issues due to its poor aqueous solubility, requiring formulation with Cremophor EL (CrEL) or ethanol (EtOH). Therefore, a CrEL-free formulation of 17-AAG was prepared using amphiphilic diblock micelles of poly(ethylene oxide)-b-poly(D,L-lactide) (PEO-b-PDLLA). Dynamic light scattering revealed PEO-b-PDLLA (12:6 kDa) micelles with average sizes of 257 nm and critical micelle concentrations of 350 nM, solubilizing up to 1.5 mg/mL of 17-AAG. The area under the curve (AUC) of PEO-b-PDLLA micelles was 1.3-fold that of the standard formulation. The renal clearance (CL(renal)) increased and the hepatic clearance (CL(hepatic)) decreased with the micelle formulation, as compared to the standard vehicle. The micellar formulation showed a 1.3-fold increase in the half-life (t(1/2)) of the drug in serum and 1.2-fold increase in t(1/2) of urine. As expected, because it circulated longer in the blood, we also observed a 1.7-fold increase in the volume of distribution (V(d)) with this micelle formulation compared to the standard formulation. Overall, the new formulation of 17-AAG in PEO-b-PDLLA (12:6 kDa) micelles resulted in a favorable 150-fold increase in solubility over 17-AAG alone, while retaining similar properties to the standard formulation. Our data indicates that the nanocarrier system can retain the pharmacokinetic disposition of 17-AAG without the need for toxic agents such as CrEL and EtOH.