Hikaru Koyama

Effects of glycosylation of hypoglycaemic drug binding to serum albumin.

The binding properties of hypoglycaemic drugs to glycosylated human serum albumin (G‐HSA) were investigated using a fluorescence quenching method. Displacement patterns between tolbutamide and Sudlows‐site‐specific drugs to G‐HSA were also investigated.

Effects of lansoprazole on pharmacokinetics and metabolism of theophylline

The effect of the new substituted benzimidazole proton pump inhibitor, lansoprazole, on pharmacokinetics and metabolism of theophylline has been studied in healthy adults given oral lansoprazole 30 mg once daily for 11 days. On Days 4 and 11 of 300 mg aminophylline was simultaneously administered orally and blood samples for theophylline analysis were taken over 24 h. Urine samples were collected for up to 24 h and were assayed for theophylline and its major metabolites 1,3-dimethyluric acid (1,3-DMU), 1-methyluric acid (1-MU) and 3-methylxanthine (3-MX). The pharmacokinetic parameters of theophylline were determined, and the urinary recovery of unchanged theophylline and its major metabolites were calculated.After administration of lansoprazole for 4 days, no significant alteration in the terminal elimination half-life (t1/2β) or the mean residence time (MRT) was detected. However, there was a significant decrease of about 13% in the area under the plasma concentration-time curve (AUC) and a significant increase of about 19% in the apparent clearance (CLapp). Lansoprazole treatment for 11 days caused a significant decrease of approximately 12% in t1/2β and about 10% in the MRT of theophylline, although neither AUC nor CLapp showed a significant alteration. The excretion of 3-MX in the urine was significantly increased by about 20% after lansoprazole treatment for 4 and 11 days, although there was no significant alteration in the excretion of unchanged theophylline, 1,3-DMU or 1-MU.The results indicate that repeated administration of lansoprazole to humans induces the hepatic microsomal P-450-dependent drug oxidation system that mediates N-1-demethylation of theophylline, consequently increasing its metabolism.

Age-related alteration of carbamazepine-serum protein binding in man.

To determine whether biological maturation influences the kinetics of carbamazepineserum protein binding, the carbamazepine free fraction (%) was investigated in the serum of 66 patients, ranging from 4 to 83 years, with epilepsy or trigeminal neuralgia, treated with carbamazepine alone or carbamazepine in combination with phenytoin, phenobarbital, and/or valproic acid, over a relatively long period.

Effect of Glycosylation on Carbamazepine‐Serum Protein Binding in Humans

Effect of glycosylation on carbamazepine‐serum protein binding was investigated in vitro using the serum from 24 diabetics and 10 healthy subjects, and in vivo using the serum from 49 patients receiving carbamazepine. In both binding studies, nonglycosylated albumin levels were strongly correlated with the carbamazepine free fraction (%). To evaluate the effect of glycosylation in vivo, the patients were divided into two groups according to glycosylated albumin levels (%): a healthy group (10–15) and a high group (15 and over). The high group had decreased nonglycosylated albumin levels and an increased carbamazepine free fraction. Our results suggest that one should not use total concentrations for the monitoring of serum carbamazepine concentrations, but free concentrations, especially in poorly controlled diabetics.

Age‐related alteration of haloperidol–serum protein binding

Serum haloperidol levels were determined in 59 patients, 50–88 years old, with psychosis, receiving long‐term treatment with haloperidol. Although the total (bound and free form) haloperidol level in serum showed a linear correlation with daily dose, there was a larger variation in the relationship between free form and the daily dose compared with total because of inter‐individual variation in the serum protein binding of haloperidol. The free fraction of haloperidol in serum increased with age. There was no difference in the ratio of total haloperidol level per daily dose between the adult and elderly groups, whereas the ratio of free haloperidol level per daily dose was significantly higher in the elderly than in the adult group. In the elderly, therefore, the therapeutic window of haloperidol should be assessed using free form level ratherthan total level, which is influenced by serum protein binding of the drug.

Age-dependent alteration of the serum-unbound fraction of nicardipine, a calcium-channel blocker, in man

To determine whether the age‐dependent increase in the pharmacological effect of calcium‐channel blockers is a result of age‐dependent alteration of the unbound fraction the drug in serum, the unbound fraction of the nicardipine was investigated in the serum of 38 adults.

Effect of Intestinal Atrophy and Hepatic Impairment Induced by Parenteral Nutrition on Drug Absorption and Disposition in Rats

BACKGROUND Long-term parenteral nutrition (PN) has a high risk of hepatic dysfunction and intestinal atrophy. The present study investigated the effect of PN-induced intestinal atrophy and hepatic impairment on drug pharmacokinetics by using 2 contrasting compounds: phenolsulfonphthalein (PSP) and cyclosporin A (CyA). MATERIALS AND METHODS PSP or CyA was administered to 7-day PN-fed Rats (PN rats) and sham operated rats (control rats) via intravenous (IV) or intraloop administration of the intestine. Pharmacokinetic parameters with 2-compartment analysis including area under the concentration vs time curve (AUC) and the permeability after in situ intraloop administration (P loop) were obtained from both concentration profiles after different administration routes. RESULTS After IV administration of PSP to control and PN rats, there was no notable difference in any of the pharmacokinetic parameters. In contrast, after intraloop administration, AUC and P loop in PN rats were approximately 2.6- and 2.0-fold higher than that in control rats, respectively. On the other hand, after IV administration of CyA, the terminal half-life and total body clearance were prolonged and decreased in PN rats, respectively, resulting in 2.0-fold increase in AUC. After intraloop administration, the AUC of PN rats was increased to approximately 1.3-fold that of control rats, whereas no notable difference was observed in P loop. CONCLUSION The intestinal permeability of PSP was enhanced by intestinal atrophy induced by PN, while the metabolism of CyA was diminished by hepatic impairment by PN. These results revealed the physicochemical property-based pharmacokinetic alterations during PN; for a more detailed understanding, however, further studies are needed.

Population Semiphysiologic Kinetic Modeling and Simulation of Plasma Triglyceride Levels After Soybean Oil–Based Intravenous Lipid Emulsion Administration in Rats:

Background: Soybean oil–based intravenous lipid emulsion (SO-ILE) has clinical utility as an energy source and in lipid rescue therapy. However, an excessive infusion rate of SO-ILE in routine use and in lipid rescue therapy may cause serious side effects. There is little information about plasma triglyceride (TG) kinetics following SO-ILE administration. The present study aimed to develop a population semiphysiologic kinetic model of TG and to predict the TG kinetics even at extremely high concentrations in rats. Materials and Methods: TG concentration profiles after intravenous bolus (0.1, 0.25, 0.5, 1.0, 1.5, and 2.0 g/kg) or infusion (3.0 g/kg/h for 1 hour) of SO-ILE to rats were analyzed by a kinetic model constructed with 4 pathways: apolipoprotein acquisitions, zero-order catabolism, first-order uptake to storage sites, and zero-order secretion from storage sites. The developed model was subjected to internal and external validation. Results: Plasma TG concentrations appeared to decline in a biphasic manner with nonlinear TG kinetics. The developed kinetic model was well validated and found to accurately predict the external validation data. Conclusions: The proposed kinetic model accurately described TG concentrations after SO-ILE administration at various infusion rates, including a lipid rescue regimen. The maximum acceptable infusion rate of SO-ILE in routine use should correspond to the maximum velocity of the apolipoprotein acquisition: 0.619 g/kg/h in rats. The prediction of TG kinetics at extremely high concentrations will provide useful information for lipid rescue therapy.