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Pharmacokinetic studies of maxacalcitol in healthy Taiwanese subjects have been conducted. This study to compare the pharmacokinetic properties of maxacalcitol in healthy Taiwanese and Japanese subjects. Healthy male Taiwanese subjects (n = 24) and healthy male Japanese subjects (n = 24) were enrolled in separate single-center and received a single intravenous dose of 1.25, 2.5 and 5 μg maxacalcitol. Male subjects were exclusively employed in the study due to the first administration of maxacalcitol to Taiwanese.Serum samples were collected for up to 72 h for pharmacokinetic analysis, and safety was assessed. Exposures to maxacalcitol as mean C5 and AUCinf appeared to increase with increase of doses in Taiwanese subjects (C5: 74.0, 159, and 321 pg/mL; AUCinf: 473, 763, and 1460 h･pg/mL) and Japanese subjects (C5: 92.9, 174, and 346 pg/mL; AUCinf: 312, 588, and 1040 h･pg/mL). After single bolus IV administration, linearity in maxacalcitol exposure was shown over the dose range of 1.25–5 μg in both Taiwanese and Japanese male healthy subjects. C5 of maxacalcitol was slightly lower (85%) in Taiwanese compared with that in Japanese and AUCinf of maxacalcitol in Taiwanese subjects was contrarily 15.0 (41.6%) higher than that in Japanese subjects, resulted in not much difference in pharmacokinetics of maxacalcitol between Taiwanese and Japanese. Moreover, maxacalcitol was well tolerated in both healthy Taiwanese and Japanese subjects.

Chao Zhang,1 Haiyan Li,2 Xin Xiong,1 Suodi Zhai,1 Yudong Wei,2 Shuang Zhang,2 Yuanyuan Zhang,1 Lin Xu,2 Li Liu1 1Department of Pharmacy, 2Institute of Clinical Trial, Peking University Third Hospital, Beijing, People’s Republic of China Abstract: We investigated the pharmacokinetics and safety profiles of a newly developed combined ethinylestradiol (EE)/gestodene (GSD) transdermal contraceptive patch after a single-dose administration and compared with the market available tablet formulation in healthy adult subjects. An open-label, two-period comparative study was conducted in 12 healthy women volunteers. A single dose of the study combined EE/GE transdermal contraceptive patch and oral tablet (Milunet®) were administered. Blood samples at different time points after dose were collected, and concentrations were analyzed. A reliable, highly sensitive and accurate high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC/MS/MS) assay method was developed in this study to determine the plasma concentrations of EE and GSD. Compared to the tablet, the study patch had a significantly decreased maximum plasma concentration (Cmax), extended time to reach the Cmax and half-life, as well as increased clearance and apparent volume of distribution. The half-lives of EE and GSD of the patch were 3.3 and 2.2 times, respectively, than the half-life of the tablet. The areas under the plasma concentration–time curve (AUCs) of EE and GSD of the patch were 8.0 and 16.2 times, respectively, than the AUC of the tablet. No severe adverse event was observed during the whole study, and the general safety was acceptable. In conclusion, compared to the oral tablet Milunet, the study contraceptive patch was well tolerated and showed potent drug exposure, significant extended half-life and stable drug concentrations. Keywords: pharmacokinetics, safety, ethinylestradiol/gestodene, transdermal contraceptive patch

An orally administered site-specific Oral Ghost Drug Delivery (OGDD) device was developed and evaluated for the administration of salmon calcitonin. In vitro drug release studies have been undertaken using biorelevant media and aspirated gastrointestinal fluid from a large white pig in addition to characterization of a formulated trimethyl chitosan blend formulated and prepared into a loaded mini-pellet system. In vivo drug release analysis in a large white pig model has further been undertaken on the OGDD device and a commercial intramuscular injection to ascertain the release properties of the OGDD device in an animal model in comparison with the currently used treatment option for the administration of salmon calcitonin. Results of this study have detailed the success of the prepared system during both in vitro and in vivo analyses with the OGDD providing a greater control of release of salmon calcitonin when compared to the commercial product. [ABSTRACT FROM AUTHOR]

Gold nanoparticles (AuNPs) have been extensively explored in biomedical applications, for example as drug carriers, contrast agents, or therapeutics. However, AuNP can exhibit cytotoxic profile, when the size is below 2 nm (ultrasmall AuNP; usAuNP) and when the stabilizing ligands allow for access to the gold surface either for the direct interaction with biomolecules or for catalytic activity of the unshielded gold surface. Furthermore, usAuNP exhibits significantly different biodistribution and enhanced circulation times compared to larger AuNP. This review gives an overview about the synthesis and the physico-chemical properties of usAuNP and, thereby, focusses on 1.4 nm sized AuNP, which are derived from the compound Au(PPh)Cl and which are the most intensively studied usAuNP in the field. This part is followed by a summary of the toxic properties of usAuNP, which include in vitro cytotoxicity tests on different cell lines, electrophysiological tests following FDA guidelines as well as studies on antibacterial effects. Finally, the biodistribution and pharmacokinetics of ultrasmall AuNP are discussed and compared to the properties of more biocompatible, larger AuNP. [ABSTRACT FROM AUTHOR]

Novel core-shell dual-mesoporous silica nanoparticles (DMSN) were successfully prepared as a carrier in order to improve the dissolution of fenofibrate and obtain an oral highly bioavailable controlled-release drug delivery system using the osmotic pump technology. Fenofibrate was loaded into DMSN by an adsorption method. The solid state properties of fenofibrate in DMSN, before and after drug loading, were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), nitrogen adsorption/desorption analysis (BET), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), X-ray powder diffraction (XRD) and differential scanning calorimetry (DSC).In vitrorelease tests showed that DMSN increased the dissolution rate of fenofibrate and produced zero-order release in push–pull osmotic pump tablets (OPT). The relative bioavailability of OPT was 186.9% in comparison with the commercial reference product. In summary, osmotic pump technology in combination with solid dispersion technology involving nanometer materials is a promising way for achieving the oral delivery of poorly water-soluble drugs. [ABSTRACT FROM AUTHOR]

1. Liver distribution and systemic exposure of pravastatin were the determinant factors of efficacy and toxicity of pravastatin. Aim of the present study was to investigate the effect of paroxetine on the liver distribution and systemic exposure of pravastatin in diabetic rats induced by combining high fat diet (HFD) and low-dose streptozotocin (STZ). 2. Plasma concentrations and liver distribution of pravastatin were measured in the presence of paroxetine. Effect of paroxetine on pravastatin excretionviabile, intestine, feces and urine, as well as pravastatin absorptionviaintestine was documented. Freshly isolated hepatocytes and Caco-2 cells were used to investigate the effect of paroxetine on pravastatin transport. 3. Paroxetine increased the systemic exposure of pravastatin and decreased hepatic distribution of pravastatin in diabetic rats.In vitro, paroxetine inhibited the hepatic uptake of pravastatin and promoted the efflux of pravastatin in freshly isolated hepatocytes, which may partly explain the decreased hepatic distribution of pravastatin by paroxetine. It was also observed that paroxetine promoted the absorption of pravastatinviajejunum and the uptake of pravastatin in Caco-2 cells. 4. We concluded that paroxetine increased the systemic exposure of pravastatin partlyviapromoting absorptionviajejunum and inhibiting hepatic uptake of pravastatin. [ABSTRACT FROM PUBLISHER]

Abstract: A transparent film-forming hydrogel formulation for tolterodine was developed using ternary phase diagram and Box-Behnken design (BBD). Carbopol 980 (neutralized by triethanolamine), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC) and Tween 80 were used as matrices. Solvent was the mixture of water and ethyl alcohol. The measured 24h cumulative drug release rate (86.02%) was consistent with the predicted value (85.42%) in mice. Steady-state flux (J) of tolterodine in optimized formulation across rat full skin, epidermal, dermis and subcutaneous tissue were 15.83, 18.55, 37.15 and 81.82μgcm−2 h−1, respectively. Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) results suggested that the hydrogels could impact lipid status in SC, which was consistent with E a (8.638kcal/mol) of tolterodine from optimized formulation in rats. In the pharmacokinetic studies, sustained-release over 24h and absolute bioavailability of the hydrogels (24.53%) was higher than tolterodine tablets (15.16%) in rats. The hydrogels were suitable for systemic administration of tolterodine for the treatment of overactive bladder. [Copyright &y& Elsevier]

Peptidomimetic drugs have favorable bioavailability owing to H+/peptide transporter 1 (PEPT1) located in the intestine. Sartans are commonly used and likely coadministered with peptidomimetic drugs in the clinic; however, in vivo interactions between sartans and peptidomimetic drugs have not been systemically understood. Herein, the effect and mechanism of sartans on the intestinal absorption and renal excretion of the dipeptide-like drug bestatin were investigated. Following oral combination with valsartan, the plasma concentration and area under the plasma concentration-time curve of bestatin in rats decreased significantly. Bestatin absorption in rat-everted intestinal sacs was dramatically reduced by valsartan. Sartans exhibited concentration-dependent inhibition on the uptake of bestatin in human PEPT1 (hPEPT1)-HeLa cells. The cumulative urinary excretion and renal clearance of the two drugs in rats decreased after intravenous coadministration. Moreover, decreased uptake of the two drugs was observed in rats' kidney slices and human organic anion transporter (hOAT)1/hOAT3-transfected cells when coadministered. The results suggest that the intestinal absorption and renal excretion of bestatin in rats were inhibited by coadministered valsartan. Interestingly, the half-maximal inhibitory concentration (IC50) values of valsartan for PEPT1 and OAT1/3 were comparable to the theoretically estimated local drug concentration and the clinical unbound concentration, respectively, proposing possible drug-drug interaction in humans via PEPT1 and OAT1/3, which should be paid particular attention when bestatin and valsartan are coadministrated clinically. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:719-729, 2014 [ABSTRACT FROM AUTHOR]

The objective of the study was to evaluate the effect of hydroxypropyl-sulfobutyl-β-cyclodextrin ( HP- SBE-β CD) on the bioavailability and intestinal absorption of edaravone, and identify its mechanism of action. We devised HP- SBE-β CD as a carrier and modulator of P-glycoprotein ( Pgp) efflux pump, and edaravone as a model drug, and prepared edaravone/ HP- SBE-β CD inclusion complex. HP- SBE-β CD improved the water solubility and enhanced the bioavailability of edaravone by 10.3-fold in rats. Then, in situ single-pass intestinal perfusion showed that HP- SBE-β CD had an effect of improving the permeability and inhibiting the efflux of edaravone. Furthermore, the effects of HP- SBE-β CD on Pgp were achieved through interfering with the lipid raft and depleting the cholesterol of enterocytes membrane. From the results, we presented the novel mechanisms. First, edaravone/ HP- SBE-β CD had a lower release from the inclusion compound to protect edaravone from the low p H of the stomach. Then, HP- SBE-β CD modulated the membrane microenvironment of intestinal absorption epithelial cells. At last, the result was that HP- SBE-β CD enhanced the absorption of edaravone by interfering with Pgp. In conclusion, HP- SBE-β CD improves the bioavailability of drug not only because of its enhancing water solubility of the drug, but also because it modulates the Pgp-mediated efflux from enterocytes. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:730-742, 2014 [ABSTRACT FROM AUTHOR]

Many currently approved drugs possess weakly basic properties that make them substrates for extensive sequestration in acidic intracellular compartments such as lysosomes through an ion trapping-type mechanism. Lysosomotropic drugs often have unique pharmacokinetic properties that stem from the extensive entrapment in lysosomes, including an extremely large volume of distribution and a long half-life. Accordingly, pharmacokinetic drug-drug interactions can occur when one drug modifies lysosomal volume such that the degree of lysosomal sequestration of secondarily administered drugs is significantly altered. In this work, we have investigated potential mechanisms for drug-induced alterations in lysosomal volume that give rise to drug-drug interactions involving lysosomes. We show that eight hydrophobic amines, previously characterized as perpetrators in this type of drug-drug interaction, cause a significant expansion in lysosomal volume that was correlated with both the induction of autophagy and with decreases in the efficiency of lysosomal egress. We also show that well-known chemical inducers of autophagy caused an increase in apparent lysosomal volume and an increase in secondarily administered lysosomotropic drugs without negatively impacting vesicle-mediated lysosomal egress. These results could help rationalize how the induction of autophagy could cause variability in the pharmacokinetic properties of lysosomotropic drugs. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:4173-4180, 2013 [ABSTRACT FROM AUTHOR]

P-glycoprotein (P-gp) is a drug efflux pump in many organs, including the intestine and liver. Two single nucleotide polymorphisms (SNPs) of P-gp gene, 2677G>T and 3435C>T, were reported to influence function and expression of P-gp and have the controversial effects on drug disposition. Phenytoin is one substrate of P-gp. Persistent low phenytoin levels in plasma and P-gp overexpression in brain in several refractory epilepsy patients were reported. P-gp polymorphisms may also affect phenytoin efficacy by altering its bioavailability ( F). Because two P-gp SNPs, 2677G>T and 3435C>T, may affect P-gp expression in tissue, we examined phenytoin disposition in patients of different P-gp haplotypes, G/G2677C/C3435 and T/T2677T/T3435. We found that the mean absolute F of phenytoin in T/T2677T/T3435 subjects (91%) is slightly higher than in G/G2677C/C3435 subjects (82%). There was no difference in the maximum concentration ( Cmax) and the area under the serum concentration-time curve of phenytoin administered orally between two genotypic groups. However, the time of maximum concentration was higher in T/T2677T/T3435 subjects (10 h) than in G/G2677C/C3435 subjects (6 h). The study ruled out the possibility that genetic polymorphisms of P-gp may affect phenytoin efficacy through the decreased absorption or the increased elimination. P-gp SNPs could affect phenytoin efficacy in refractory epilepsy patients probably because of central nervous system. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3189-3195, 2013 [ABSTRACT FROM AUTHOR]

US Food and Drug Administration (FDA) has identified innovation in clinical evaluations as a major scientific priority area. This paper provides case studies and updates to describe the efforts by the FDA's Office of Clinical Pharmacology in its development and application of regulatory science, focusing on modeling and simulation. Key issues and challenges are identified that need to be addressed to promote the uptake of modeling and simulation approaches in drug regulation. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. 102:2912-2923, 2013 [ABSTRACT FROM AUTHOR]

Allometric scaling has been applied to the pharmacokinetics (PK) of factor VIII (FVIII), but published relationships are based on relatively small subsets of available data. Numerous next-generation forms of FVIII are being developed (e.g., Fc fusion, PEGylated, and liposomal formulations) and traditional PK scaling of these products would not incorporate the wealth of existing knowledge for current FVIII therapy in humans. We conducted a meta-analysis and developed allometric relationships of FVIII from over 100 PK studies collected from literature. Normalized Wajima curves were used to relate mean FVIII profiles between species. An 'informed scaling' approach was derived for predicting first-in-human PK parameters and demonstrated with a case study for an Fc fusion FVIII. NCA values for FVIII PK were well described by the allometric equations CL = 6.59 W0.85 and Vss = 65.0 W0.97. A subset of studies characterized by two-compartment modeling showed strong linearity in scaling of total clearance (CL) and central volume, but more variability in distributional CL and peripheral volume. Wajima curves for FVIII superimposed across species and the disposition of Fc fusion FVIII in humans was well predicted by 'informed scaling.' This approach might be generally applicable for predicting human PK of next-generational therapeutics. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2380-2394, 2013 [ABSTRACT FROM AUTHOR]

The acetaminophen dosage schedule in pediatric patients below 12 years of age for the over-the-counter (OTC) monograph is one of the many issues being evaluated and discussed in the development of the Proposed Rule for Internal Analgesic, Antipyretic, and Anti-rheumatic drug products. The dosage regimen based on age and weight, with instructions that weight-based dosage should be used if a child's weight is known, is currently being assessed by the agency. This review summarizes the available pharmacokinetic and pharmacodynamic (fever reduction) data of oral acetaminophen in pediatric patients of 6 months to 12 years of age. Acetaminophen is metabolized in the liver mainly through glucuronidation, sulfation, and to a lesser extent oxidation. Because of the difference in the ontogeny of various metabolizing pathways, the relative contribution of each pathway to the overall acetaminophen metabolism in children changes with age. The sulfation pathway plays a more important role in metabolizing acetaminophen than the glucuronidation pathway in younger children as compared with older children and adults. The pharmacokinetic exposure of acetaminophen in pediatric patients of 6 months to 12 years of age given oral administration of 10-15 mg/kg is within the adult exposure range given the OTC monograph dose. The antipyretic effect of acetaminophen is dose dependent and appears to be better than placebo at the dose range of 10-15 mg/kg in pediatric patients of 6 months to 12 years of age. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:4383-4389, 2012 [ABSTRACT FROM AUTHOR]

Terminologies for describing dosage form release characteristics for human pharmaceuticals have been addressed by bodies such as the US Food and Drug Administration (FDA), the International Conference on Harmonization (ICH), and the US Pharmacopeia (USP). While the definition for terms such as “immediate release,” “modified release,” “extended release,” and “delayed release” are now well accepted for human pharmaceuticals, confusion still exists within the veterinary community. In part, this confusion is attributable to differences between human and veterinary dosage forms (such as the preponderance of parenteral vs. oral extended release products for use in animals vs. the focus on oral extended release formulations for human use) which reflect interspecies differences in physiology and conditions of use. It also simply reflects a lack of attention to existing definitions. In an effort to remedy this problem, this manuscript reflects an initial effort to suggest definitions that may be appropriate for describing formulation effects in veterinary medicine. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3281–3290, 2010 [ABSTRACT FROM AUTHOR]

Although, no credible data are available, it is widely believed that the pharmacokinetic parameters such as clearance, volume of distribution, and elimination half-life can be scaled with a fixed exponent of 0.75, 1.0, and 0.25, respectively. However, logically it is difficult to perceive that the exponents of allometry for a given parameter will revolve around a fixed number. Over the last 80 years, theoretical biologists and physiologists are entangled in an argument whether the exponent of basal metabolic rate against body weight is 0.67 or 0.75. There are evidence for and against these two exponents. However, in-depth investigative works suggest that there is not really any universal exponent for any allometrically related parameter and the exponent of allometry depends on several factors. The main focus of this report is to show the readers that there is enough evidence from experimental data that negate the notion of fixed exponents in biology, physiology, and pharmacokinetics. In short, the notion of a fixed exponent is theoretical and there is no evidence that the exponent of a physiological or pharmacokinetic parameter revolves around a fixed number. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:2927–2933, 2010 [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the in vitro and in vivo interactions between flavonoids and P-glycoprotein (P-gp) substrates. The inhibitory effects of flavonoids on P-gp were determined by accumulation studies in P-gp-overexpressing MCF-7/ADR cells using daunomycin (DNM) as a model substrate. Morin, phloretin, biochanin A, chalcone, and silymarin significantly increased DNM accumulation by greater than 2.5-fold, suggesting they are P-gp inhibitors. To explore potential in vivo interactions of flavonoids with P-gp, the effect of biochanin A on the pharmacokinetics of the P-gp substrates doxorubicin, cyclosporine A, and paclitaxel was investigated. In contrast to the in vitro results, intraperitoneal or oral administration of biochanin A did not significantly change the pharmacokinetics of doxorubicin and cyclosporine A. Moderate interaction was observed between biochanin A and paclitaxel, resulting in lower AUC values after both i.v. and oral administration of paclitaxel. The disconnect between the in vitro and in vivo data suggests that P-gp interactions mediated by biochanin A may be limited due to its poor bioavailability and rapid clearance. It is also possible that other transporters or metabolizing enzymes are more important in the in vivo disposition of doxorubicin, cyclosporine A, and paclitaxel than P-gp. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:430–441, 2010 [ABSTRACT FROM AUTHOR]

In the treatment of cardiac arrhythmias, amiodarone (AM) has emerged as a primary therapeutic agent. In addition to other cytochrome P450 (CYP), 1A1 and 1A2 facilitate the biotransformation of AM to the pharmacologically and toxicologically active metabolite, desethylamiodarone (DEA). The exposure to polycyclic aromatic hydrocarbons can induce these isoforms. This study was aimed at investigating the effect of CYP1A induction on the disposition of AM, after single and multiple intravenous doses, using β-naphthoflavone (BNF) treated rats to model induction of CYP1A. After a single dose (25 mg/kg), the plasma AUC of DEA were significantly induced (∼3-fold). With multiple doses, AM AUC0–24 h was significantly reduced in the BNF plasma (30%), lung (35%), liver (48%), kidney (52%), heart (34%), and intestine (43%). In contrast the DEA AUC0–24 h was increased significantly in the BNF plasma (36%), lung (56%), liver (101%), kidney (65%), and heart (73%). The DEA/AM ratios of the AUC0–24 h were increased in the BNF plasma, lung, liver, kidney, and heart by 1.9-, 2.5-, 3.8-, 3.4-, and 2.7-fold, respectively. In both groups of rats, the highest concentrations of AM and DEA were in the lung. Exposure to BNF was shown to increase DEA concentrations in the rat. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:539–548, 2010 [ABSTRACT FROM AUTHOR]

Conclusions based on either in vitro or in vivo approach to evaluate the P-gp affinity status of opioids may be misleading. For example, in vitro studies indicated that fentanyl is a P-gp inhibitor while in vivo studies indicated that it is a P-gp substrate. Quite the opposite was evident for meperidine. The objective of this study was to evaluate the P-gp affinity status of methadone, buprenorphine and diprenorphine to predict P-gp-mediated drug-drug interactions and to determine a better candidate for management of opioid dependence. Two in vitro (P-gp ATPase and monolayer efflux) assays and two in vivo (tissue distribution and antinociceptive evaluation in mdr1a/b (-/-) mice) assays were used. Methadone stimulated the P-gp ATPase activity only at higher concentrations, while verapamil and GF120918 inhibited its efflux (p < 0.05). The brain distribution and antinociceptive activity of methadone were enhanced (p < 0.05) in P-gp knockout mice. Conversely, buprenorphine and diprenorphine were negative in all assays. P-gp can affect the PK/PD of methadone, but not buprenorphine or diprenorphine. Our report is in favor of buprenorphine over methadone for management of opioid dependence. Buprenorphine most likely is not a P-gp substrate and concerns regarding P-gp-mediated drug-drug interaction are not expected. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4928–4940, 2009 [ABSTRACT FROM AUTHOR]

Oral administration is the most desirable route of drug delivery for systemically active drugs. Oral drugs must possess a certain level of oral bioavailability, which is a product of oral absorption and first-pass effect. Low oral bioavailability may be attributed to poor absorption and/or high first-pass hepatic elimination. In the lead optimization stage of drug discovery, if the relative contribution of oral absorption and metabolism could be discerned for poorly bioavailable compounds, a path forward for remedy would be possible. This report describes an approach utilizing oral/intravenous pharmacokinetic data to estimate oral absorption. The fraction of dose absorbed is calculated as the ratio of the actual bioavailable fraction to the maximum bioavailable fraction estimated from systemic clearance. An arbitrary classification was devised where low absorption encompasses compounds whose extent of absorption is ≤20%, moderate is for those between 21% and 69%, and high is for those that show ≥70% absorption. There was approximately 78% concordance in rats, 65% in monkeys and almost complete concordance in dogs. This approach correctly identified the cause for low oral bioavailability for 11 out of 13 compounds evaluated, and therefore it could be used prospectively with nonradiolabeled compounds during the lead optimization process. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4027–4038, 2009 [ABSTRACT FROM AUTHOR]

In order to elucidate the causes of the species differences in the oral bioavailability (BA) between cynomolgus monkeys and humans, the contributions of first-pass metabolism and intestinal absorption were investigated. Typical substrates of cytochrome P450 enzymes, UDP-glucuronosyltransferase enzymes and efflux transporters were selected, and the BA, the hepatic availability (Fh) and the fraction dose absorbed from gastro-intestinal tract (Fa*Fg) were calculated from pharmacokinetic analysis after oral and intravenous administration in cynomolgus monkeys. In addition, in vitro metabolism was investigated using liver and intestinal microsomes to evaluate the relationship between in vivo and in vitro results. The BA of cynomolgus monkeys was low compared with that in humans with most of the drugs tested, and not only Fh but also Fa*Fg contributed significantly to the low BA in cynomolgus monkeys. When Fh was evaluated in in vitro experiments, it correlated well with the in vivo Fh. However, although the metabolic activities of CYP3A4 substrates were high in cynomolgus monkey intestinal microsomes, those of the other substrates were low or not detected. These findings suggested that the species differences and low BA in cynomolgus monkeys could be mostly attributed not only to hepatic first-pass metabolism but also to the intestinal absorption process. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4343–4353, 2009 [ABSTRACT FROM AUTHOR]

Polyethylene glycol (PEG) polymers are large amphiphilic molecules that are highly hydrated in solution. To explore the permeability properties of different sized PEG polymers across epithelial membranes in vivo, we examined the absorption of fluorescently labeled PEG conjugates sized 0.55–20 kDa from the lung, since this system provides a reservoir that limits rapid diffusion of molecules away from the site of delivery and enables permeability over longer times to be examined. Following intratracheal delivery in rats, the PEG polymers underwent absorption with first-order kinetics described by single exponential decay curves. PEG size produced a marked influence on the rate of uptake from the lung, with half-lives ranging from 2.4 to 13 h, although above a size of 5 kDa, no further change in rate was observed. PEG size likewise affected retention in alveolar macrophages and in lung tissue; whereas smaller PEG sizes (<2 kDa) were effectively cleared within 48 h, larger PEG sizes (>5 kDa) remained in lung cells and tissue for up to 7 days. These data demonstrate that PEG polymers can be absorbed across epithelial membranes and that PEG size plays a dominant role in controlling the rate and mechanism of absorption. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2847–2856, 2009 [ABSTRACT FROM AUTHOR]

The effect of hyperlipidemia on the biodistribution of (±)-halofantrine (HF) was studied in rats. Plasma, adipose, and highly perfused tissues heart, lung, liver, kidney, spleen and brain were harvested for up to 48 h after dosing animals with 2 mg/kg (±)-HF intravenously by tail vein. Stereospecific HPLC was used to measure HF and desbutyl-HF (DHF) enantiomer concentrations. Plasma concentrations of both HF enantiomers in hyperlipidemic (HL) exceeded those in normolipidemic (NL) rats by 11- to 15-fold. Significant increases in AUC of both HF enantiomers were noted in HL spleen tissue whereas decreases were seen in HL lung and fat. In rest of the tissues either decreases or no changes were noted in HL. The concentrations of DHF were very low in NL and HL plasma but were much higher in all highly perfused tissues. Both HF and DHF enantiomers shifted from lipoprotein deficient fraction to triglyceride-rich fractions in HL plasma following in vitro incubation of the respective racemic compounds. Compared to NL, no significant differences were noted in HF metabolism to DHF in HL liver microsomes. It would appear that both reduced plasma unbound fraction and lipoprotein associated directed uptake of lipoprotein-bound drug by tissues play roles in enantiomer biodistribution. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2516–2528, 2009 [ABSTRACT FROM AUTHOR]

Aim: To evaluate the effects of cyclosporin A and itraconazole, which were used as inhibitors of P-glycoprotein (P-gp) and/or cytochrome P450 (CYP) 3A4 on the pharmacokinetics of atorvastatin in rats. Methods: The pharmacokinetic parameters of atorvastatin were measured after intravenous (2 mg/kg) and intra-gastric (10 mg/kg) administration of atorvastatin in rats, which were pretreated with cyclosporin A (5, 10, and 20 mg/kg) or itraconazole (5, 10, and 20 mg/kg). Results: Compared with the control rats, cyclosporin A and itraconazole altered the pharmacokinetics of atorvastatin significantly. The AUC0-t values of atorvastatin after intragastric administration, pretreated with cyclosporin A (5–20 mg/kg), increased by 32.3%, 61.8%, and 187.2%, respectively, but the CLbile values decreased ( P<0.01, 5–20 mg/kg). With pretreatment of itraconazole (5–20 mg/kg), the AUC0-t values of atorvastatin increased by 88.2%, 102%, and 123%, respectively, but the CLbile values decreased ( P<0.01, 5–20 mg/kg). Conclusion: These data indicated that cyclosporin A could be effective in inhibiting the efflux of atorvastatin, and itraconazole could be effective in inhibiting both the metabolism and biliary excretion of atorvastatin. [ABSTRACT FROM AUTHOR]

Acetyl-L-carnitine (ALC), a naturally occurring endogenous compound, has been shown to improve the cognitive performance of patients with senile dementia Alzheimer’s type, and to be involved in cholinergic neurotransmission. Because ALC is an endogenous compound, validation of the analytical methods of ALC in the biological fluids is very important and difficult. This study was presented validation and correction for plasma ALC concentrations and pharmacokinetics after oral administration of ALC to human volunteers. ALC concentrations in human plasma were corrected by subtracting the concentration of blank plasma from each sample. Precision and accuracy (bias %) for uncorrected ALC concentrations were below 2.6 and 6.5% for intra-days, and 4.0 and 9.4% for inter-days, respectively. Precision and accuracy (bias %) for corrected ALC concentrations were below 10.9 and 6.0% for intra-days, and 10.5 and 16.9% for inter-days, respectively. Quantitation limit was 0.1 ¼g/mL. After oral administration of a 500 mg ALC tablet to 8 healthy volunteers, the principle pharmacokinetic parameters were 4.2 h of the half-life (t1/2,β), the area under the curve (AUC0→8) of 9.88 ¼gh/mL, and 3.1 h of the time (Tmax) to reach Cmax. This study first describes the pharmacokinetic study after oral administration of a single dose of ALC in human volunteers. [ABSTRACT FROM AUTHOR]

Pharmacokinetic studies of maxacalcitol in healthy Taiwanese subjects have been conducted. This study to compare the pharmacokinetic properties of maxacalcitol in healthy Taiwanese and Japanese subjects. Healthy male Taiwanese subjects (n = 24) and healthy male Japanese subjects (n = 24) were enrolled in separate single-center and received a single intravenous dose of 1.25, 2.5 and 5 μg maxacalcitol. Male subjects were exclusively employed in the study due to the first administration of maxacalcitol to Taiwanese. Serum samples were collected for up to 72 h for pharmacokinetic analysis, and safety was assessed. Exposures to maxacalcitol as mean C 5 and AUC inf appeared to increase with increase of doses in Taiwanese subjects (C 5 : 74.0, 159, and 321 pg/mL; AUC inf : 473, 763, and 1460 h･pg/mL) and Japanese subjects (C 5 : 92.9, 174, and 346 pg/mL; AUC inf : 312, 588, and 1040 h･pg/mL). After single bolus IV administration, linearity in maxacalcitol exposure was shown over the dose range of 1.25-5 μg in both Taiwanese and Japanese male healthy subjects. C 5 of maxacalcitol was slightly lower (85%) in Taiwanese compared with that in Japanese and AUC inf of maxacalcitol in Taiwanese subjects was contrarily 15.0 (41.6%) higher than that in Japanese subjects, resulted in not much difference in pharmacokinetics of maxacalcitol between Taiwanese and Japanese. Moreover, maxacalcitol was well tolerated in both healthy Taiwanese and Japanese subjects., (© 2020 Chugai Pharmaceutical Co. Ltd. Published by Elsevier Ltd.)