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Background and objectives: Hyzetimibe is a candidate drug being investigated as the second-in-class cholesterol absorption inhibitor; it lowers plasma levels of low-density lipoprotein cholesterol (LDL-C) by blocking the Niemann-Pick C1-like 1 protein, a transporter mainly expressed in the intestine that allows dietary cholesterol to enter the body from the intestinal lumen. Previous studies on the metabolism of hyzetimibe in healthy volunteers were not enough to show the biotransformation and excretion pathway; in particular, whether hyzetimibe maintains pharmacological action for duration sufficient to pass through the hepatic-intestinal circulation remains unknown. Furthermore, it remains unclear whether the differences between the chemical structures of ezetimibe and hyzetimibe would result in different pharmacokinetic characteristics. Given that the molecular target is in the intestine and the substantial hepatic-intestinal circulation is a metabolic characteristic of the drug, a study of hyzetimibe as an oral 14C-radiolabeled drug, compared with routinely metabolized drugs, would play an important role in uncovering pharmacokinetic details.Methods: After an overnight fast and before taking medication, six healthy male volunteers swallowed an investigational product suspension containing 20 mg/∼100 μCi of 14C-labeled hyzetimibe as a single dose. Whole-blood, plasma, urine, and fecal samples were collected, and hyzetimibe and its metabolites were measured. Pharmacokinetic variables of hyzetimibe and its metabolites were calculated and statistically analyzed according to obtained concentration data. Safety data were collected throughout the study.Results: The major metabolite detected in plasma was hyzetimibe-glucuronide, which accounted for 97.2% of the total plasma radioactivity. The mean cumulative excretion of total radioactivity of the dose was 16.39% in urine and 76.90% in feces. Unchanged drug and hyzetimibe-glucuronide were identified as the major components in the feces and the urine, respectively. The main metabolic conversions of hyzetimibe were glucuronidation (M1), mono-oxidation (M4), and mono-oxidation with additional sulfonation (M7). Hyzetimibe was considered generally safe and well tolerated.Conclusion: This study of 14C-radiolabeled hyzetimibe provides a full profile of the biotransformation and excretion routes of hyzetimibe to improve the understanding of the pharmacokinetic characteristics of hyzetimibe. The changed hydroxyl group in the hyzetimibe structure made it easier for that drug, compared with ezetimibe, to combine with glucuronic acid and subsequently increased the urinary excretion of hyzetimibe vs. ezetimibe. These differences highlight the need to investigate in more detail the different pharmacokinetic impacts on the efficacy and safety of hyzetimibe and ezetimibe.

Background and objectives: Hyzetimibe is a candidate drug being investigated as the second-in-class cholesterol absorption inhibitor; it lowers plasma levels of low-density lipoprotein cholesterol (LDL-C) by blocking the Niemann-Pick C1-like 1 protein, a transporter mainly expressed in the intestine that allows dietary cholesterol to enter the body from the intestinal lumen. Previous studies on the metabolism of hyzetimibe in healthy volunteers were not enough to show the biotransformation and excretion pathway; in particular, whether hyzetimibe maintains pharmacological action for duration sufficient to pass through the hepatic-intestinal circulation remains unknown. Furthermore, it remains unclear whether the differences between the chemical structures of ezetimibe and hyzetimibe would result in different pharmacokinetic characteristics. Given that the molecular target is in the intestine and the substantial hepatic-intestinal circulation is a metabolic characteristic of the drug, a study of hyzetimibe as an oral 14C-radiolabeled drug, compared with routinely metabolized drugs, would play an important role in uncovering pharmacokinetic details. Methods: After an overnight fast and before taking medication, six healthy male volunteers swallowed an investigational product suspension containing 20 mg/∼100 μCi of 14C-labeled hyzetimibe as a single dose. Whole-blood, plasma, urine, and fecal samples were collected, and hyzetimibe and its metabolites were measured. Pharmacokinetic variables of hyzetimibe and its metabolites were calculated and statistically analyzed according to obtained concentration data. Safety data were collected throughout the study. Results: The major metabolite detected in plasma was hyzetimibe-glucuronide, which accounted for 97.2% of the total plasma radioactivity. The mean cumulative excretion of total radioactivity of the dose was 16.39% in urine and 76.90% in feces. Unchanged drug and hyzetimibe-glucuronide were identified as the major components in the feces and the urine, respectively. The main metabolic conversions of hyzetimibe were glucuronidation (M1), mono-oxidation (M4), and mono-oxidation with additional sulfonation (M7). Hyzetimibe was considered generally safe and well tolerated. Conclusion: This study of 14C-radiolabeled hyzetimibe provides a full profile of the biotransformation and excretion routes of hyzetimibe to improve the understanding of the pharmacokinetic characteristics of hyzetimibe. The changed hydroxyl group in the hyzetimibe structure made it easier for that drug, compared with ezetimibe, to combine with glucuronic acid and subsequently increased the urinary excretion of hyzetimibe vs. ezetimibe. These differences highlight the need to investigate in more detail the different pharmacokinetic impacts on the efficacy and safety of hyzetimibe and ezetimibe. [ABSTRACT FROM AUTHOR]

A series of novel niosomes with the amphiphilic copolymer of poly (methoxy-polyethyleneglycol cyanoacrylate-co-n-hexadecyl cyanoacrylate) (PEG-PHDCA) acted as surface modification materials were prepared and Hydroxycamptothecin (HCPT) was used as a model drug. This work concentrated on the effects of PEG chain length and particle sizes on the niosomes surface properties, in vitro drug release, phagocytic uptake, in vivo pharmacokinetics and antitumor activity. Within the range of PEG Mw from 2000 to 10000, the increasing zeta potential (from -16.08 to -5.25 mv) and thicker fixed aqueous layer (3.82 to 5.78 nm) would facilitate the niosomes' stealth effects, while the reduced PEG chain density (from 0.53 to 0.17 PEG/nm2) and the quickened speed of drug release would diminish the effects. As a result, the PEG5000-PHDCA niosomes had the least phagocytic uptake, the longest half-life of 11.46 h and the best tumor inhibition rate of 97.1%. In the groups different in particle size (PEG5000-PHDCA niosomes from 92.5 to 204.6 nm), the bigger particles could be uptaken by macrophages more quickly, regardless of the changes of other physicochemical parameters. Correspondingly, PEG5000-PHDCA niosomes with particle sizes of 92.5, 144.2, 204.6 nm could extend the half-life of HCPT to 11.46, 6.33, 4.46 h, respectively. At last, the tumor inhibition rate of PEG5000-PHDCA niosomes (92.5 nm) at a dose of 2 mg/kg was five times that of HCPT injection at 4 mg/kg.The stealth effects of the PEG-PHDCA niosomes and the enhanced stability of lactone form of HCPT were accountable for the powerful antitumor effects of niosomes. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95: 1873–1887, 2006 [ABSTRACT FROM AUTHOR]

In recent years there have been tremendous strides in understanding the relationship between the pharmacodynamics of β-lactams and microbiologic response. For β-lactams, in vitro and animal studies suggest that the amount of time in which free or non-protein-bound antimicrobial concentration exceeds the minimum inhibitory concentration (MIC) of the organism (fT>MIC) is the best predictor of bacterial killing and microbiologic response. Using population pharmacokinetic modeling and Monte Carlo simulation, it is possible to integrate pharmacokinetics, a pharmacodynamic target, and microbiologic surveillance data to generate empiric β-lactam dosing strategies that maximize the likelihood of achieving fT>MIC associated with nearmaximal bactericidal effect against the range of pathogens encountered in clinical practice. At Albany Medical Center Hospital, these mathematical modeling techniques were used to devise alternative dosing schemes for piperacillin-tazobactam, meropenem, and cefepime. These ahernative schemes optimized fT>MIC at a lower total daily dose than would be employed with traditional dosing methods. Moreover, they achieved the targeted fT>MIC with less administration time/day than would be needed for continuous infusion. [ABSTRACT FROM AUTHOR]