Haruki Kinoshita

Effect of Oily Vehicles on Absorption of Mepitiostane by the Lymphatic System in Rats

Abstract— [14C]Mepitiostane in various vehicles was administered to the small intestine of anaesthetized rats with cannulated thoracic ducts, and the effect of lipids on lymphatic absorption was examined. The extent of lymphatic absorption was greatest when administered in triolein and sesame oil, which are triglycerides of long‐chain fatty acids. Absorption in the presence of other vehicles was in the order of 10% Tween 80 aqueous solution > monolein > oleic acid ∼ oleic acid/monolein (2:1 mol/mol) > aqueous suspension. Differences between the extents of lymphatic absorption of mepitiostane in the various formulations were not due to variation in the lymph flow but to the increased secretion of chylomicron and very low density lipoproteins. During absorption of mepitiostane from the small intestine, oil affected not only the penetration into epithelium cells and the metabolism in them, but also the partition between blood and lymph.

Pharmacokinetic and Pharmacodynamic Analysis of Subcutaneous Recombinant Human Granulocyte Colony Stimulating Factor (Lenograstim) Administration

A total of 72 adult healthy volunteers were administered 1 μg/kg of rhG‐CSF. There was no correlation between Cmax and an increase in peripheral neutrophil count, and there was a negative correlation between AUC and this increase. The mechanism of this is probably based on the correlation between the elimination rate constant (ke) and neutrophil increase. The ke probably has a close relationship with uptake by neutrophil and its progenitor via the G‐CSF receptor. An individual with higher ke should therefore show a greater increase in neutrophil count. Therefore, AUC is proportional to the rhG‐CSF remainder, that is, the proportion that is not consumed in the course of increasing the neutrophil count. In such a situation, the bioavailability calculated from the AUC is unlikely to indicate the absorbed amount. The authors also analyzed the pharmacokinetics using a two‐compartment model with zero‐order absorption and first‐order elimination. This model was sufficient to obtain a good curve fit, and this demonstrates that the absorption process is not a first‐order but a zero‐order process. Therefore, there might be an upper limit to the rhG‐CSF transfer rate from subcutaneous tissue to blood.

Effect of Bile on Absorption of Mepitiostane by the Lymphatic System in Rats

Abstract— The effects of bile and site of gastrointestinal absorption on the lymphatic absorption of the highly lipophilic drug, mepitiostane were examined using thoracic duct‐cannulated rats. The lymphatic absorption from the small intestine was very small in the absence of bile compared with that when bile was present. The lymphatic absorption was greatest when drug was administered to the upper small intestine with bile, was smaller for the lower regions of the small intestine, and was negligible for the stomach and the large intestine. A correlation was observed between the extent of lymphatic absorption and the secretion of chylomicron and very low density lipoproteins after administration to various regions with or without bile. The portal absorption data of mepitiostane confirmed that site specificity occurs in the partition of drug between blood and lymph.

Intrinsic lymphatic partition rate of mepitiostane, epitiostanol, and oleic acid absorbed from rat intestine.

Mepitiostane (MP), epitiostanol (EP), and oleic acid were administered to the jejunal loop of mesenteric vein- and thoracic duct-cannulated rats, and the intrinsic lymphatic partition rate (ILPR) of the absorbed compounds was directly determined. When 14C-EP was administered to the jejunal loop, recovery of unchanged EP in the mesenteric blood and the lymph was 7.9 and 0.03% of the administered dose, respectively. In contrast, following administration of 14C-MP, recovery of unchanged MP in the mesenteric blood and the lymph was 1.2 and 15.0%, respectively. Thus, following passage through the mucosal cell, 99.6% of the unchanged EP was partitioned into the blood and 0.4% into the lymph, while for unchanged MP, 7.6% was partitioned into the blood and 92.4% into the lymph. When 14C-oleic acid was administered to the jejunal loop, most of the penetrating oleic acid was incorporated into triglycerides in epithelial cells and transferred exclusively into the lymph. However, of the unchanged oleic acid, only 37.6% was partitioned into the lymph and 62.4% into the blood. The ILPR was 92.4% for MP, 0.4% for EP, and 37.6% for oleic acid. We conclude that the ILPR values indicate the true lymphotropic property of the compounds.

Prediction of human blood-to-plasma drug concentration ratio.

The objective of this study was to predict Rb (blood/plasma ratio) in humans using a simple method. Human and rat Rb and free fraction in plasma (fp) values were obtained from the literature. The ratio of total red blood cell concentration to the free concentration in plasma (Kb) was calculated using fp and Rb. Four methods were used for the prediction of Rb: (A) use of rat Rb; (B) use of Rb calculated from rat Kb and human fp; (C) correlation of human log ((1−fp)/fp) and human log Kb; and (D) correlation of log D with human log Kb. The Rb of 96 compounds in humans ranged from 0.52 to 2.00, with an average of 0.89. A significant correlation was observed among human log Kb, human log ((1−fp)/fp), and log D; however, no obvious correlation was observed among human Rb, human log ((1−fp)/fp), and log D. The errors within 1.25‐fold for methods A–D were 68.3%, 77.6%, 61.5% and 64.8%, respectively. All predictive methods considered here were superior to the use of the average value of human Rb or Rb=1. Rat Rb corrected by human fp improved the accuracy of the prediction. Method B was the most accurate of the four methods. Copyright

Estimation of rhG-CSF absorption kinetics after subcutaneous administration using a modified Wagner-Nelson method with a nonlinear elimination model.

The clearance of recombinant human granulocyte-colony stimulating factor (rhG-CSF) is known to decrease with dose increase, and to be saturable. The average clearance after intravenous administration will be lower than that after subcutaneous administration. Therefore, the apparent absolute bioavailability with subcutaneous administration calculated from the AUC ratio is expected to be an underestimate. The absorption pharmacokinetics after subcutaneous administration was examined using the results of the bioequivalency study between two rhG-CSF formulations with a dose of 2 microg/kg. The analysis was performed using a modified Wagner-Nelson method with the nonlinear elimination model. The apparent absolute bioavailability for subcutaneous administration was 56.9 and 67.5% for each formulation, and the ratio between them was approximately 120%. The true absolute bioavailability was, however, estimated to be 89.8 and 96.9%, respectively, and the ratio was approximately 108%. The absorption pattern was applied to other doses, and the predicted clearance values for subcutaneous and intravenous administrations were then similar to the values for several doses reported in the literature. The underestimation of bioavailability was around 30%, and the amplification of difference was 2.5 times, from 8 to 20%, because of the nonlinear pharmacokinetics. The neutrophil increases for each formulation were identical, despite the different bioavailabilities. The reason for this is probably that the amount eliminated through the saturable process, which might indicate the amount consumed by the G-CSF receptor, was identical for each formulation.

Population pharmacokinetic and pharmacodynamic modelling of the effects of nicorandil in the treatment of acute heart failure

AIMS The aims of the study were 1) to evaluate the pharmacokinetics of nicorandil in healthy subjects and acute heart failure (AHF) patients and 2) to evaluate the exposure-response relationship with pulmonary arterial wedge pressure (PAWP) in AHF patients and to predict an appropriate dosing regimen for nicorandil. METHODS Based on the data from two healthy volunteer and three AHF patient studies, models were developed to characterize the pharmacokinetics and pharmacodynamics of nicorandil. PAWP was used as the pharmacodynamic variable. An asymptotic exponential disease progression model was used to account for time dependent changes in PAWP that were not explained by nicorandil exposure. The modelling was performed using NONMEM version V. RESULTS The pharmacokinetics of nicorandil were characterized by a two-compartment model with linear elimination. CL, V1 and V2 in AHF patients were 1.96, 1.39 and 4.06 times greater than in healthy subjects. Predicted plasma concentrations were assumed to have an immediate concentration effect relationship on PAWP. An inhibitory E(max) model with E(max) of -11.7 mmHg and EC(50) of 423 microg l(-1) was considered the best relationship between nicorandil concentrations and PAWP. PAWP decreased independently of nicorandil exposure. This drug independent decline was described by an asymptotic decrease of 6.1 mmHg with a half-life of 5.3 h. CONCLUSIONS AHF patients have higher clearance and initial distribution volume of nicorandil compared with healthy subjects. The median target nicorandil concentration to decrease PAWP by 30% is predicted to be 748 microg l(-1), indicating that a loading dose of 200 microg kg(-1) and a maintenance dose of 400 microg kg(-1) h(-1) would be appropriate for the initial treatment of AHF.

The pharmacokinetics of ceftriaxone based on population pharmacokinetics and the prediction of efficacy in Japanese adults

SummaryObjective: By using a population pharmacokinetic analysis method, we predicted the efficacy of Ceftriaxone (CTRX) based on the pharmacokinetics of CTRX in Japanese adults and the sensitivity of infective organisms to CTRX in 2004. In addition, we clarified the difference in efficacy between once-a-day administration and twice-a-day administration. Methods: The population pharmacokinetic analysis was based on the serum concentrations of CTRX already published by NONMEM. The possible effect of body weight and age on the pharmacokinetics of CTRX was examined using a model which incorporated the change of a specific protein-binding ratio of CTRX. A Monte Carlo simulation was conducted based on the population pharmacokinetic parameters obtained by this analysis, and thereby the time above MIC (TAM) was determined from the MIC values of CTRX administered once at 0.5, 1, and 2 g and twice at 1 g. The efficacy ratio was predicted from the TAM thus obtained. Results: Because the time course of serum concentration of CTRX in adult subjects was fitted to a 2-compartment model and both body weight and age were not incorporated as the covariate, the dosing method by which a fixed amount of CTRX is administered to patients has been thought to be adequate. Based on the efficacy ratio estimated from the MIC of CTRX, we have predicted that the once-a-day administration of CTRX even at 0.5g is effective on various infecting organisms.

EPIMERIZATION OF MOXALACTAM BY ALBUMIN AND SIMULATION OF IN VIVO EPIMERIZATION BY A PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL

We investigated the mechanism of epimerization (R to S or S to R) of moxalactam in serum of rats, dogs, and humans. The epimerization of moxalactam occurred in the serum of these animals, but not in the serum filtrate. The albumin fraction of human serum purified by gel filtration catalysed the epimerization of moxalactam at an identical rate to serum, but other fractions (i.e., lipoproteins and globulins) showed slower epimerization. alpha 1-acid glycoprotein, which was eluted in the same fraction with albumin by G-200 gel filtration, did not epimerize moxalactam. The presence of 2 mM warfarin decreased the binding of R- and S-moxalactam and decreased the epimerization of moxalactam in human serum. These results demonstrate moxalactam was epimerized on the warfarin binding site on albumin in serum. Additionally, a physiologically based pharmacokinetic model shows that the epimerization of moxalactam after administration in dogs is simulated by the epimerization in serum.

The relationship between hepatic microsomal biphenyl 2-hydroxylase, 4-hydroxylase and urinary glucaric acid excretion in the rat

SummaryTreatment of rats with phénobarbital (PB) caused an increase in microsomal biphenyl 4-hydroxylase activity and urinary glucaric acid excretion. Hepatic microsomal biphenyl 4-hydroxylase activity was correlative with urinary glucaric excretion in PB-treated rats.Hepatic microsomal biphenyl 2-hydroxylase activity was not correlated with urinary glucaric excretion in PB, 3-methylcholanthrene (3-MC)- and β-naphthoflavone (β-NF)-treated rats.Pretreatment of rats with carbon tetrachloride caused decreases in urinary glucaric acid excretion and biphenyl 2- and 4-hydroxylase activities. On the other hand, pretreatment with cobalt chloride caused decreases of these enzyme activities, but not of urinary glucaric acid excretion.These findings suggest that the urinary glucaric acid level would not always provide an index for assessment of hepatic drug metabolizing enzyme activity.These findings suggest that the urinary glucaric acid level would not always provide an index for assessment of hepatic drug metabolizing enzyme activity.