Nose-to-brain delivery of TS-002, prostaglandin D2 analogue

This study was conducted to investigate the possibility of performing nose-to-brain delivery of TS-002, which is an analog compound of prostaglandin D2 (PGD2) and thus would be a natural sleep inducer. The absolute bioavailability (BA) and sleep-inducing effect (SIE) following intranasal (IN) administration of TS-002 dry powder to cynomolgus monkeys were evaluated in comparison with intravenous (IV) administration. The SIE was evaluated as the accumulated time of sleeping-posture for 3 h. The brain distribution of TS-002 following IN administration of the dry powder was examined in rats. The absolute bioavailability (BA) in monkeys following IN administration of the dry powder (0.4-1.2 mg/body) was comparatively high (43.4-78.0%). The SIE following IN administration (0.05-0.4 mg/body) showed dose-dependency and its effect at 0.4 mg/body was twice as strong as that for IV administration (P < 0.05). The brain concentrations in rats following IN administration (0.1 mg/kg) were obviously higher than that for IV administration at the same dose. The highest content was observed in the olfactory bulb. These results demonstrated that TS-002 was directly transported from the olfactory region to brain, thereby showing that it may be possible to develop a novel sleep-inducing drug based on nose-to-brain delivery.     

Systemic and direct nose-to-brain transport pharmacokinetic model for remoxipride after intravenous and intranasal administration

Intranasal (IN) administration could be an attractive mode of delivery for drugs targeting the central nervous system, potentially providing a high bioavailability because of avoidance of a hepatic first-pass effect and rapid onset of action. However, controversy remains whether a direct transport route from the nasal cavity into the brain exists. Pharmacokinetic modeling is proposed to identify the existence of direct nose-to-brain transport in a quantitative manner. The selective dopamine-D2 receptor antagonist remoxipride was administered at different dosages, in freely moving rats, by the IN and intravenous (IV) route. Plasma and brain extracellular fluid (ECF) concentration-time profiles were obtained and simultaneously analyzed using nonlinear mixed-effects modeling. Brain ECF/plasma area under the curve ratios were 0.28 and 0.19 after IN and IV administration, respectively. A multicompartment pharmacokinetic model with two absorption compartments (nose-to-systemic and nose-to-brain) was found to best describe the observed pharmacokinetic data. Absorption was described in terms of bioavailability and rate. Total bioavailability after IN administration was 89%, of which 75% was attributed to direct nose-to brain transport. Direct nose-to-brain absorption rate was slow, explaining prolonged brain ECF exposure after IN compared with IV administration. These studies explicitly provide separation and quantitation of systemic and direct nose-to-brain transport after IN administration of remoxipride in the rat. Describing remoxipride pharmacokinetics at the target site (brain ECF) in a semiphysiology-based manner would allow for better prediction of pharmacodynamic effects.     

Demonstration of Nucleoside Transporter Activity in the Nose-to-Brain Distribution of [<Superscript>18</Superscript>F]Fluorothymidine Using PET Imaging

To evaluate the role of nucleoside transporters in the nose-to-brain uptake of [¹⁸F]fluorothymidine (FLT), an equilibrative nucleoside transporter (ENT1,2) and concentrative nucleoside transporter (CNT1–3) substrate, using PET to measure local tissue concentrations. Anesthetized Sprague-Dawley rats were administered FLT by intranasal (IN) instillation or tail-vein injection (IV). NBMPR (nitrobenzylmercaptopurine riboside), an ENT1 inhibitor, was administered either IN or intraperitoneally (IP). Dynamic PET imaging was performed for up to 40 min. A CT was obtained for anatomical co-registration and attenuation correction. Time-activity curves (TACs) were generated for the olfactory bulb (OB) and remaining brain, and the area-under-the-curve (AUC) for each TAC was calculated to determine the total tissue exposure of FLT. FLT concentrations were higher in the OB than in the rest of the brain following IN administration. IP administration of NBMPR resulted in increased OB and brain FLT exposure following both IN and IV administration, suggesting that NBMPR decreases the clearance rate of FLT from the brain. When FLT and NBMPR were co-administered IN, there was a decrease in the OB AUC while an increase in the brain AUC was observed. The decrease in OB exposure was likely the result of inhibition of ENT1 uptake activity in the nose-to-brain transport pathway. FLT distribution patterns show that nucleoside transporters, including ENT1, play a key role in the distribution of transporter substrates between the nasal cavity and the brain via the OB.     

Pharmacokinetics and dose-dependency of LB30870 in rats, dogs, and monkeys

This study was to examine the pharmacokinetics of LB30870, a thrombin inhibitor, after IV and oral administration to rats, dogs, and monkeys. In rats and dogs, LB30870 showed linear pharmacokinetics after IV and oral administration. The oral bioavailability (BA) in rats was about 30 % with high inter-subject variability in the time to reach peak plasma concentration (T_max). Oral absorption of a solution and prototype tablet formulations of LB30870 were tested in dogs. T_max was 30 min and the BA values were 40.8–43.1 % with solution formulation. BA values after oral administration of the two tablet formulations at the dose of 100 mg/dog were 27.0 and 30.8 %. T_max were 60 min in the tablet formulation, indicating that the disintegration and dissolution of tablets caused delay in T_max compared to solution formulation. After IV administration of LB30870 to monkeys, the plasma concentrations decreased bi-exponentially and BA was 15.0 % after oral (20 mg/kg) dosing. In summary, linear pharmacokinetics of LB30870 were observed in both rats and dogs. The differences in BA among species could be due to difference in absorbed fraction and/or the first pass extraction (pre-systemic elimination) of LB30870.     

Pharmacokinetics and brain penetration study of chlorogenic acid in rats

1. The present study is designed to investigate the brain distribution and plasma pharmacokinetics profiles of chlorogenic acid (CGA) after intranasal administration in Charles–Foster rats to evaluate whether the CGA molecules are transported directly via the nose-to-brain path.

2. The CGA is administered intravenously (IV) and intranasally (IN) at the dose of 10?mg/kg. Further, its concentration in the plasma, cerebrospinal fluid (CSF) and the whole brain is analyzed by HPLC-UV method.

3. The study observes that CGA is rapidly absorbed in plasma with t_max of 1?min similar to IV route after IN administration. The peak plasma concentration and AUC_0–24 are higher by 3.5 and 4.0 times respectively in IV administration, compared to IN delivery that represents the significant less systemic exposure of CGA in IN route.

4. However, the concentration of CGA in the brain is 4, 6.5, 5.3, 5.2 and 4.5 times higher at 30, 60, 120, 240 and 360?min, respectively in IN administration compared to IV administration. The exposure of CGA in the brain after IN administration (AUC_{brain, IN}) was significantly greater (4 times) as compared to the exposure of CGA in the brain (AUC_{brain, IV}) after IV administration reflecting significant brain uptake of CGA through nasal route. Therefore, IN delivery of CGA can be a promising approach for the treatment of stroke and neurodegenerative disorders.     

Brain distribution of ribavirin after intranasal administration

Ribavirin has proved to be effective in vitro against several RNA viruses responsible for encephalitis in humans and animals. However, the in vivo efficacy towards the cerebral viral load seems to be limited by the blood–brain barrier. Since the nose-to-brain pathway has been indicated for delivering drugs to the brain, we investigated here the distribution of ribavirin in the central nervous system (CNS) after intranasal administration. We first tested in vitro ribavirin diffusion from an aqueous solution across a biological membrane, using Franz cells and rabbit nasal mucosa. About 35% of ribavirin permeated in 4 h across the mucosa, after reaching steady-state flux in less than 30 min. In the first in vivo experiment, ribavirin aqueous solution was administered intranasally to Sprague Dawley rats (10 mg/kg). Animals were sacrificed at 10, 20 or 30 min after administration to collect brain areas (cerebellum, olfactory bulb, cerebral cortex, basal ganglia and hippocampus) and biological fluids (cerebrospinal fluid and plasma). Ribavirin, quantified by LC–MS/MS spectrometry, was detected at each time point in all compartments with the highest concentration in olfactory bulb and decreasing in rostro-caudal direction. Two subsequent in vivo experiments compared the nasal route (ribavirin solution) with the intravenous one and the nasal administration of ribavirin solution with ribavirin powder (10 mg/kg). It was found that 20 min after administration, ribavirin concentration in olfactory bulb was similar after intravenous or nasal administration of the ribavirin solution, whereas the powder led to significantly higher levels. Ribavirin was also present in deeper compartments, such as basal ganglia and hippocampus.Even if the mechanisms involved in ribavirin nose-to-brain transport are not clear, these results suggest a rapid extracellular diffusive flux from the nasal epithelium to the olfactory bulb and different CNS areas.     

Pharmacokinetics of midazolam in children: comparative study of intranasal and intravenous administration

Summary Twelve children 1–5 y old were randomly assigned to receive midazolam 0.2 mg·kg^–1 either by the intravenous (IV) or intranasal (IN) routes.After IN administration the rapid onset of absorption was observed (t_max 12 min). After both routes of administration the half-life was similar (2.2 h IN and 2.4 h IV). After IN administration the apparent plasma clearance and volume of distribution were about twice as high as after IV administration.The results are consistent with an estimated mean bioavailability of 55%.     

Brain distribution of ribavirin after intranasal administration

Ribavirin has proved to be effective in vitro against several RNA viruses responsible for encephalitis in humans and animals. However, the in vivo efficacy towards the cerebral viral load seems to be limited by the blood–brain barrier. Since the nose-to-brain pathway has been indicated for delivering drugs to the brain, we investigated here the distribution of ribavirin in the central nervous system (CNS) after intranasal administration. We first tested in vitro ribavirin diffusion from an aqueous solution across a biological membrane, using Franz cells and rabbit nasal mucosa. About 35% of ribavirin permeated in 4 h across the mucosa, after reaching steady-state flux in less than 30 min. In the first in vivo experiment, ribavirin aqueous solution was administered intranasally to Sprague Dawley rats (10 mg/kg). Animals were sacrificed at 10, 20 or 30 min after administration to collect brain areas (cerebellum, olfactory bulb, cerebral cortex, basal ganglia and hippocampus) and biological fluids (cerebrospinal fluid and plasma). Ribavirin, quantified by LC–MS/MS spectrometry, was detected at each time point in all compartments with the highest concentration in olfactory bulb and decreasing in rostro-caudal direction. Two subsequent in vivo experiments compared the nasal route (ribavirin solution) with the intravenous one and the nasal administration of ribavirin solution with ribavirin powder (10 mg/kg). It was found that 20 min after administration, ribavirin concentration in olfactory bulb was similar after intravenous or nasal administration of the ribavirin solution, whereas the powder led to significantly higher levels. Ribavirin was also present in deeper compartments, such as basal ganglia and hippocampus.Even if the mechanisms involved in ribavirin nose-to-brain transport are not clear, these results suggest a rapid extracellular diffusive flux from the nasal epithelium to the olfactory bulb and different CNS areas.     

Microdialysis evaluation of the brain distribution of stavudine following intranasal and intravenous administration to rats

Intranasal (IN) administration as a potential route of enhancing brain delivery of stavudine (d4T) was investigated in rats using microdialysis as a sampling technique. Sprague-Dawley rats were divided into two groups (n = 7 per group). One group of animals received IN administration of 5 mg/kg d4T (50 microL); the other group was dosed intravenously (IV) at the same dose. Following IN administration, d4T was rapidly and completely absorbed into the systemic circulation with a T(max) of 14 min and an IN bioavailability of 105%. The brain/plasma AUC ratios in the lateral ventricle, caudate putamen, and frontal cortex in the anesthetized and nasal surgery-operated rats were 0.36 +/- 0.090, 0.47 +/- 0.089, and 0.41 +/- 0.087, respectively, whereas they were 0.63 +/- 0.077, 0.62 +/- 0.17, 0.60 +/- 0.13, respectively, following IV dosing to sham animals. The half-life of d4T in the various brain regions was significantly longer than that in plasma (p < 0.05). Moreover, the systemic clearance of d4T was significantly reduced in these anesthetized and nasal surgery-operated animals. Further studies of the effect of anesthesia suggest the additive role of anesthesia, possibly in additional to nasal surgery, in decreasing the systemic clearance. The extent of the brain distribution, however, was not significantly affected by anesthesia. Lack of enhancement of the brain delivery of d4T following IN administration over systemic dosing cannot be attributed to its absorption into systemic circulation, since direct nose-brain transport, if fully functional and effective, should be a parallel and competing process with systemic absorption. The current study results along with several physiological considerations raise a question regarding the overall effectiveness of IN administration for direct delivery of small molecules into brain tissues, particularly where passive diffusion predominates.     

Pharmacokinetics of Ethionamide Delivered in Spray-Dried Microparticles to the Lungs of Guinea Pigs

The use of ethionamide (ETH) in treating multidrug-resistant tuberculosis is limited by severe side effects. ETH disposition after pulmonary administration in spray-dried particles might minimize systemic exposure and side effects. To explore this hypothesis, spray-dried ETH particles were optimized for performance in a dry powder aerosol generator and exposure chamber. ETH particles were administered by the intravenous (IV), oral, or pulmonary routes to guinea pigs. ETH appearance in plasma, bronchoalveolar lavage, and lung tissues was measured and subjected to noncompartmental pharmacokinetic analysis. Dry powder aerosol generator dispersion of 20% ETH particles gave the highest dose at the exposure chamber ports and fine particle fraction of 72.3%. Pulmonary ETH was absorbed more rapidly and to a greater extent than orally administered drug. At T_max, ETH concentrations were significantly higher in plasma than lungs from IV dosing, whereas insufflation lung concentrations were 5-fold higher than in plasma. AUC_(0-t) (area under the curve) and apparent total body clearance (CL) were similar after IV administration and insufflation. AUC_(0-t) after oral administration was 6- to 7-fold smaller and CL was 6-fold faster. Notably, ETH bioavailability after pulmonary administration was significantly higher (85%) than after oral administration (17%). These results suggest that pulmonary ETH delivery would potentially enhance efficacy for tuberculosis treatment given the high lung concentrations and bioavailability.     

Pharmacokinetics and brain uptake of diazepam after intravenous and intranasal administration in rats and rabbits

The purpose of this study was to investigate the plasma pharmacokinetics and brain uptake of a lipophilic benzodiazepine anticonvulsant, diazepam in New Zealand white rabbits and Sprague-Dawley rats to evaluate the possible absorption pathways after intravenous and intranasal administration. The intranasal formulation was prepared by dissolving DZ and 1% sodium glycocholate into microemulsion system composed of 15% ethyl laurate, 25% Labrasol, 37.5% Transcutol P, 12.5% ethanol, and 10% water. Diazepam was administered intravenously (1 mg/kg) or intranasally (2 mg/kg) to rats and rabbits. Drug concentrations in the plasma and six different regions of the brain tissues, i.e., olfactory bulb, olfactory tract, anterior, middle, and posterior segments of cerebrum and cerebellum were analyzed by LC/MS method after solid phase extraction. After i.n. administration, DZ was rapidly absorbed into the systemic circulation, and readily and homogeneously distributed into the different regions of brain tissues with a t(max) of 5 and 10 min in rats and rabbits, respectively. The bioavailability of DZ in rat plasma (68.4%) and brain (67.7%) were 32-47% higher than those observed in rabbit plasma (51.6%) and brain (45.9%). The AUC(brain)/AUC(plasma) ratios in rabbits after i.n. administration (3.77+/-0.17) were slightly lower than from i.v. administration (4.23+/-0.08). However, in rats the AUC(brain)/AUC(plasma) ratios after i.v. (3.03+/-0.07) and i.n. (3.00+/-0.32) administration were nearly identical. The plasma pharmacokinetic and distribution studies in the two animal models clearly showed that lipophilic DZ molecules reached the brain predominantly from the blood by crossing the blood-brain barrier after i.n. administration with no significant direct nose-to-brain transport via olfactory epithelium.     

Physiological modeling and assessments of regional drug bioavailability of danoprevir to determine whether a controlled release formulation is feasible

Danoprevir, a potent, selective inhibitor of HCV NS3/4A protease, has a short half‐life in humans. Therefore, the feasibility of a controlled release (CR) formulation to allow less frequent dosing was investigated using experimental approaches and physiological modeling to examine whether danoprevir is absorbed in the colon. Danoprevir absorption was studied in portal‐vein‐cannulated monkeys and in monkeys surgically modified to make intraduodenal, intrajejunal, intracolonic and oral administration possible. In portal‐vein‐cannulated monkeys, absorption was apparent up to 24 h after administration. The observed relative bioavailability from intracolonic delivery in the monkey was approximately 30% relative to oral administration, consistent with the model prediction of 40%. Human relative bioavailability for a tablet delivered to the colon compared with an immediate release (IR) formulation was predicted to be 4–28%. Preclinical data and modeling suggested that CR development would be challenging for this Biopharmaceutics Classification System Class IV compound. Therefore, a confirmative study in healthy volunteers was conducted to investigate the relative bioavailability of danoprevir in various regions of the gastrointestinal tract. In a randomized, open‐label, crossover study, subjects received 100 mg danoprevir IR soft gel capsule, 100 mg danoprevir solution delivered to the distal small bowel and colon via an Enterion? capsule (a remotely activated capsule for regional drug delivery) and 100 mg danoprevir powder to the colon via an Enterion? capsule. The relative bioavailability of danoprevir (compared with IR) delivered to the colon was 6.5% for a solution and 0.6% for a powder formulation, indicating that a CR formulation is not feasible. Copyright © 2011 John Wiley & Sons, Ltd.     

Pharmacoimaging of Blood-Brain Barrier Permeable (FDG) and Impermeable (FLT) Substrates After Intranasal (IN) Administration

To illustrate the use of imaging to quantify the transfer of materials from the nasal cavity to other anatomical compartments, specifically, transfer to the brain using the thymidine analogue, [¹⁸F]fluorothymidine (FLT), and the glucose analogue, [¹⁸F]fluorodeoxyglucose (FDG). Anesthetized rats were administered FLT or FDG by intranasal instillation (IN) or tail-vein injection (IV). PET/CT imaging was performed for up to 60 min. Volumes-of-interest (VOIs) for the olfactory bulb (OB) and the remaining brain were created on the CT and transferred to the co-registered dynamic PET. Time-activity curves (TACs) were generated and compared. The disposition patterns were successfully visualized and quantified and differences in brain distribution patterns were observed. For FDG, the concentration was substantially higher in the OB than the brain only after IN administration. For FLT, the concentration was higher in the OB than the brain after both IN and IV and higher after IN than after IV administration at all times, whereas the concentration in the brain was higher after IN than after IV administration at early times only. Approximately 50 and 9% of the IN FDG and FLT doses, respectively, remained in the nasal cavity at 20 min post-administration. The initial phase of clearance was similar for both agents (t1/2?=?2.53 and 3.36 min) but the slow clearance phase was more rapid for FLT than FDG (t1/2?=?32.1 and 85.2 min, respectively). Pharmacoimaging techniques employing PET/CT can be successfully implemented to quantitatively investigate and compare the disposition of radiolabeled agents administered by a variety of routes.     

Modification of the Fc Region of a Human Anti‐oncostatin M Monoclonal Antibody for Higher Affinity to FcRn Receptor and Extension of Half‐life in Cynomolgus Monkeys

The purpose of this study was to evaluate the pharmacokinetics (PK) of anti‐oncostatin M (OSM) IgG1 monoclonal antibodies, CNTO 1119 and its Fc variant (CNTO 8212), which incorporates the LS(Xtend) mutation to extend terminal half‐life (T_1/2), after a single intravenous (IV) or subcutaneous (SC) administration in cynomolgus monkeys, and to predict human PK. In study 1, single doses of CNTO 1119 and CNTO 8212 were administered IV or SC at 3 mg/kg to cynomolgus monkeys (n = 3 per group). In study 2, single doses of CNTO 8212 were administered IV at 1, 5 or 20 mg/kg, or SC at 5 mg/kg to cynomolgus monkeys (n = 5 per group). Serial blood samples were collected for assessment of serum concentrations of CNTO 1119 and/or CNTO 8212. A two‐compartment population PK model with first‐order elimination was utilized to simultaneously describe the serum concentrations of CNTO 1119 and CNTO 8212 over time after IV and SC administration in cynomolgus monkeys. The typical population PK parameter estimates for CNTO 1119 in cynomolgus monkeys were clearance (CL) = 2.81 mL/day/kg, volume of distribution of central compartment (V₁) = 31.3 mL/kg, volume of distribution of peripheral compartment (V₂) = 23.3 mL/kg, absolute bioavailability (F) = 0.84 and T_1/2 = 13.4 days. In comparison, the typical population PK parameter estimates for CNTO 8212 in cynomolgus monkeys were CL = 1.41 mL/day/kg, V₁ = 39.8 mL/kg, V₂ = 32.6 mL/kg, F = 0.75 and T_1/2 = 35.7 days. The mean CL of CNTO 8212 was ~50% lower compared with that for CNTO 1119 in cynomolgus monkeys. The overall volume of distribution (V₁+V₂) for CNTO 8212 was about 32% larger compared with that for CNTO 1119, but generally similar to the vascular volume in cynomolgus monkeys. The T_1/2 of CNTO 8212 was significantly (p < 0.05) longer by about 2.7‐fold than that for CNTO 1119 in cynomolgus monkeys. Thus, the modification of the Fc portion of an anti‐OSM IgG1 mAb for higher FcRn binding affinity resulted in lower systemic clearance and a longer terminal half‐life in cynomolgus monkeys. CNTO 8212 demonstrated linear PK after a single IV dose (1–20 mg/kg) in cynomolgus monkeys. The predicted human PK parameters suggest that CNTO 8212 is likely to exhibit slow clearance and long terminal half‐life in human beings and may likely allow less frequent dosing in the clinical setting.     

In‐situ absorption,protein binding and pharmacokinetic studies of S002‐853, a novel antidiabetic and antidyslipidaemic flavone derivative in rats

Objectives The aim of the study was to investigate the in‐situ absorption kinetics, plasma protein binding and pharmacokinetic characteristics of a novel synthetic flavone derivative, S002‐853, which shows pronounced antidiabetic and antidyslipidaemic activity. Methods Quantification of S002‐853 in plasma was performed by the LC‐MS/MS method and in‐situ sample analysis was carried out by the HPLC‐UV method. Key findings The absorption rate constant was 0.274/h in a mild alkaline environment, which S002‐853 experiences in the intestine following oral dose administration. Plasma protein binding was found to be 26.37 ± 2.58% at a concentration of 1 μg/ml. The pharmacokinetic parameters were determined in male rats after administration of a single 40 mg/kg oral dose and 10 mg/kg intravenous dose. The peak plasma concentration (C_max) was found to be 60.93 ng/ml at 8 h after oral administration. Irregular concentration–time profiles with secondary peaks were observed after oral dose administration. The elimination half‐life of the compound was 19.56 h and 16.30 h after oral and intravenous doses, respectively. Comparison of the AUC after oral and intravenous dosing of S002‐853 indicates that only about 29.48% (bioavailability) of the oral dose reaches the systemic circulation. Conclusions In‐situ study of S002‐853 shows slow absorption from the gastrointestinal tract. S002‐853 also shows low plasma protein binding. The pharmacokinetic parameters after oral and intravenous dose reveal low oral bioavailability and high mean residence time.     

Microdialysis pharmacokinetic study of scopolamine in plasma,olfactory bulb and vestibule after intranasal administration

The purpose of this study was to investigate the microdialysis pharmacokinetic of scopolamine in plasma, olfactory bulb and vestibule after intranasal administration. The pharmacokinetic study of subcutaneous and oral administration was also performed in rats. From the in vivo results, scopolamine intranasal administration can avoid hepatic first-pass effect. T_max plasma samples after intranasal administration were significantly faster than oral administration and subcutaneous injection. The relative bioavailability of intranasal administrations was 51.8–70% when compared with subcutaneous injection. Moreover, one can see that in comparison with scopolamine subcutaneous administration, scopolamine intranasal gel and solutions can increased drug target index (DTI) with olfactory bulb 1.69 and 2.05, vestibule 1.80 and 2.15, respectively. The results indicated that scopolamine can be absorbed directly through the olfactory mucosa into the olfactory bulb, and then transported to various brain tissue after intranasal administration, with the characteristics of brain drug delivery.     

Differences in nonclinical pharmacokinetics between species and prediction of human pharmacokinetics of TAK‐272 (SCO‐272), a novel orally active renin inhibitor

In the search for orally available drugs, the prediction of human pharmacokinetics (PK) is essential for successfully selecting compounds that will be clinically useful. This report describes the selection of TAK‐272 (SCO‐272), a novel orally active renin inhibitor, as a clinical candidate via the detailed investigation of nonclinical PK data and human PK prediction. The bioavailability (BA) of TAK‐272 after oral administration to rats and monkeys was low, especially in fasted monkeys, and the systemic exposure of TAK‐272 was highly variable in monkeys. The results of mass balance studies in animals suggested that the absorbed TAK‐272 was largely eliminated by metabolism. In vitro studies revealed that TAK‐272 was mainly metabolized by CYP3A4/5 in humans, and it was a P‐glycoprotein substrate. PK analysis suggested that the factors responsible for the low BA were different in rats and monkeys. First‐pass hepatic extraction was high in rats, while the fraction absorbed from the gastrointestinal tract (F_a * F_g) was low in monkeys. It was predicted that humans would have a higher BA and a longer half‐life in the plasma compared with the animals by a simple calculation using intrinsic hepatic clearance in monkeys, which correlates well with human values for CYP3A4 substrates, and F_a * F_g in rats, which correlates relatively well with human values. TAK‐272 was finally selected as a clinical candidate based on the result of human PK prediction. The actual human PK after oral administration of TAK‐272 was comparable to the predicted profile and was preferable for clinical usage.     

Rapid Absorption of Dry-Powder Intranasal Oxytocin

Purpose

To probe the suitability of a dry-powder oxytocin formulation containing a carrier (μco?; SNBL, Ltd.) for intranasal (IN) administration to treat post-partum hemorrhage in the developing world. Specifically, to investigate (1) whether IN administration can achieve rapid systemic absorption in cynomolgus monkeys, and (2) whether the formulation exhibits sufficient physical and chemical stability. This study was conducted to support Merck for Mothers, Merck’s 10-year global initiative to end preventable maternal deaths.

Methods

A partial-crossover pharmacokinetic (PK) study in cynomolgus monkeys (n?=?6) was utilized to compare in vivo absorption of dry-powder IN oxytocin at three dose levels against an IM injection of an aqueous oxytocin formulation. Particle size distribution, delivered dose and chemical assay were monitored over a 12 month stability study.

Results

IN administration of oxytocin resulted in short (5 min) T_max and good dose linearity in AUC and C_max over the dose range tested (10–80 IU per animal). The relative bioavailability (BA) of IN oxytocin to IM injection was approximately 12%. The 80 IU formulation exhibited good physical stability and consistent dosing. After 12 months at 30°C/65%RH, pouched samples retained 86.0% of their original assay value.

Conclusions

The PK and stability data suggests that IN administration of oxytocin formulated in the μco? carrier may represent a viable option for rapid systemic absorption in humans and a product compatible with resource-scarce regions.

     

Pharmacokinetics of a new antitumor 3-arylisoquinoline derivative, CWJ-a-5

The lungs are useful for administration of macromolecules, which are poorly absorbed from the intestine. In the present study, we prepared several dry powder formulations of insulin using a spray drying technique to examine the effect of additives on insulin absorption. The bioavailability of insulin was estimated from the change in the plasma glucose level. The bioavailability of insulin from dry powder with no additive exceeded that obtained from pH 7.4 solution. The absolute bioavailability of insulin administered as a solution with 1.4 mg/dose of bacitracin or 1.0 mg/dose of Span 85 was almost 100%. The bioavailability of dry powder with 0.42 mg/dose of bacitracin was 20% that of the solution with 1.4 mg/dose of bacitracin. The insulin dry powder with 0.21 mg/dose of Span 85 showed a bioavailability less than that for the insulin solution with 0.1 mg/dose of Span 85. Bacitracin and Span 85 were not as effective in dry powder as in solution in the present study. While citric acid was more effective in dry powder that in solution to increase the hypoglycemic effect. The pH 5.0 and pH 3.0 solutions containing 0.19 mg of citric acid in 0.1 ml showed absolute bioavailabilities of 43% and 57%, respectively, while the bioavailabilities for dry powders containing 0.025 and 0.036 mg/dose citric acid were 42% and 53%, respectively. In addition, the hypoglycemic effect of dry powders continued for a longer period and remained at 240 min with the dry powders, while it disappeared at 180 min with the solutions. When the insulin dry powder containing 0.036 mg/dose of citric acid was administered, the lactate dehydrogenase activity, a sensitive indicator of acute toxicity to lung cells, in bronchoalveolar lavage was as low as that for saline administration, suggesting citric acid is a safe additive. Thus, citric acid appears to be a safe and potent absorption enhancer for insulin in dry powder.     

Oxidative stress-mediated neurotoxicity of cadmium

Young albino rats were administered cadmium i.p. (0.4 mg/kg body weight) for a period of 30 days and membrane fluidity, intracellular calcium level, MDA level, phospholipids, (phosphatidylethanolamine, phosphatidylcholine, phosphatidylinositol, phosphatidylserine and sphingomyelin) and reduced glutathione were studied in olfactory bulb, cerebellum and rest of brain. A decrease in membrane fluidity was observed in all the brain regions studied, maximum being in olfactory bulb (21%). Intracellular calcium (Ca⁺⁺)₁ level was increased significantly in olfactory bulb (150%) followed by rest of brain (98%) and cerebellum (71%) in Cd-exposed rats in comparison with controls. A significant decrease in phosphatidylcholine (27%) and phosphatidylethanolamine (22%) was observed in olfactory bulb, while other phospholipids remained unaffected. TBA reactivity was increased in olfactory bulb (77%), cerebellum (35%) and rest of brain (27%). Reduced glutathione level was also decreased in different brain regions. The results suggest that the effect of cadmium in brain is region-specific and most pronounced in olfactory bulb.