Nobuyuki Sugioka

Determination of a new immunosuppressant, mycophenolate mofetil, and its active metabolite, mycophenolic acid, in rat and human body fluids by high-performance liquid chromatography

Mycophenolate mofetil, a new immunosuppressant, is a morpholinoethyl ester of mycophenolic acid. A new selective, sensitive and simple high-performance liquid chromatographic method was developed for the determination of mycophenolic acid and mycophenolate mofetil in biological samples. The preparation of samples was based on liquid-liquid extraction. The compounds were separated on a CN column using acetonitrile-0.01 M phosphate buffer (1:4, v/v) as the mobile phase. UV detection was used at wavelengths 215 and 304 nm. The detection limit was 5 ng per injection volume. This method enabled pharmacokinetic and pharmacodynamic studies in humans and rats.

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.

Effect of plasma lipid on pharmacokinetics of ciclosporin and its relationship with plasma prednisolone level in renal transplant patients

Ciclosporin (cyclosporine A, CyA) is a potent immunosuppressant used after organ transplantation. The pharmacokinetic properties of CyA vary widely and lipoproteins are the major complexing constituents for CyA in the plasma. Therefore, a change in lipoprotein level may influence the pharmacokinetic properties of CyA. Prednisolone (PSL) is concomitantly used with CyA as an immunosuppressant. After organ transplantation, hyperlipidaemia resulting from PSL therapy has been mostly observed and PSL increased the plasma lipoprotein level. Therefore, in this study, to obtain more useful information of the therapeutic drug monitoring (TDM) of CyA, the relationship between the plasma PSL level, plasma lipoprotein level and blood CyA level was investigated in detail. An open‐label, non‐randomized, retrospective study was performed. Data from 21 male and 11 female patients (age 11–65 years) who received a living‐related renal transplantation from 2002 to 2004 were included. On postoperative days (PODs) 7, 14 and 28, the area under the plasma concentration‐time curve until 9 h after 40 mg of PSL administration (AUCPSL400–9) correlated well with total cholesterol (T‐cho) (r = 0.558, 0.768, 0.660, all P < 0.05) and high‐density lipoprotein (HDL) (r = 0.688, P < 0.05; 0.835, P < 0.01; 0.508, P < 0.05), and correlated negatively with very‐low‐density lipoprotein (VLDL) (r = −0.486, P < 0.01; −0.776, P < 0.01; −0.967, P < 0.01). In addition, AUC until 9 h after CyA administration (AUCCyA0–9) also correlated with T‐cho (r = 0.797, P < 0.01; 0.577, P < 0.05; 0.901, P < 0.01), HDL (r = 0.514, P < 0.05; 0.614, P < 0.05; 0.893, P < 0.01) and low‐density lipoprotein (LDL) (r = 0.906, P < 0.01; 0.573, P < 0.05; 0.537, P < 0.05), and there was a negative correlation with VLDL (r = −0.480, −0.630, −0.632, all P < 0.05). Moreover, AUCCyA0–9 correlated well with AUCPSL400–9 (r = 0.728, P < 0.01; 0.482, P < 0.05; 0.688, P < 0.05); namely, it was considered that the variety of plasma PSL concentrations influenced the pharmacokinetic properties of CyA through the change in lipoprotein levels. These results suggested that monitoring of the biochemical parameters of the plasma lipid and plasma PSL level might be useful for the TDM of CyA.

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.

Estimation of minimum whole-blood tacrolimus concentration for therapeutic drug monitoring with plasma prednisolone concentration: A retrospective cohort study in Japanese kidney transplant recipients

BACKGROUND In immunosuppressive therapy administered after organ transplantation, therapeutic drug monitoring (TDM) of tacrolimus must be performed frequently because of the large variation in its pharmacokinetic properties and a progressive decrease in dose requirements. An indicator for estimating the target minimum whole-blood tacrolimus concentration (Cmin TAC) would be useful to minimize the number of blood samplings required for tacrolimus TDM. OBJECTIVES The primary objective of this study was to investigate whether plasma prednisolone concentration, postoperative days (POD) and AUC 0 to 9 hours before transplantation (AUC0-9int) are useful indicators of tacrolimus TDM. The secondary objective was to determine the usefulness of blood tacrolimus concentration as an indicator of the development of nontraumatic, glucocorticoid-induced necrosis of the femoral head, an adverse event that has been associated with the use of prednisolone in vivo. METHODS This open-label, nonrandomized, retrospective study was conducted at the Department of Transplantation and Regenerative Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan. Data from 43 male and 22 female patients (mean age, 38 years [range, 9-64 years]) who received a living-related kidney transplant from 2001 to 2004 were included. Multiple blood samplings were performed to determine AUC0-9int, AUC 0 to 9 hours after drug administration and after transplantation (AUC0-9), Cmin TAC, Cmax, and Tmax after transplantation. The correlations between each parameter were determined. The correlation between POD and the changes in tacrolimus bioavailability was investigated using the indicator, defined as the tacrolimus dose required to maintain the target (10-15 ng/mL) Cmin TAC (dose/C10-15). Correlations between dose/C10-15 and AUC0-9int (3 AUC0-9int groups, defined as follows: low, medium, and high [<93, ≧93-≤152, and ≧152 ng·h/mL, respectively]) were determined. Correlations between mean Cmin values of prednisolone at a dose of 40 mg on PODs 4 to 11 (Cmin PSL40) and Cmin TAC, or AUC0-9int were determined. A subanalysis was used to determine the relationship between dose/C10-15 and the prevalence of nontraumatic, glucocorticoid-induced necrosis of the femoral head. RESULTS Cmin TAC was found to be significantly correlated with AUC0-9int (r=0.554; P<0.001) and Cmin PSL40 (r=0.336; P<0.001). In the low-AUC0-9int group, dose/C10-15 was higher than that of the other groups (P<0.001). AUC0-9int was significantly correlated with Cmin PSL40 (r=0.445; P<0.001)). Dose/C10-15 in the patient group that had necrosis of the femoral head was lower than that of the group without necrosis (n=6; P<0.01). CONCLUSIONS The results of this small, retrospective study suggest that Cmin PSL40, AUC0-9int, and POD were significant predictors of Cmin TAC. These parameters were found to be a useful indicator of tacrolimus TDM in these Japanese transplant recipients. Our results also suggest that dose/C10-15 and AUC0-9int might be useful indicators for estimating the risk for nontraumatic, steroid-induced necrosis of the femoral head. (Curr Ther Res Clin Exp. 2006;67: 103-117) Copyright