Influence of ABCB1 C3435T polymorphism on the pharmacokinetics of lansoprazole and gastroesophageal symptoms in Japanese renal transplant recipients classified as CYP2C19 extensive metabolizers and treated with tacrolimus.

OBJECTIVE: Lansoprazole and tacrolimus are substrates of ATP binding cassette (ABC) transporters such as P-glycoprotein (ABCBI/multidrug resistance 1) and cytochrome P450 (CYP). The purpose of this study was to investigate the implication of the ABCB1 C3435Tpolymorphism on the pharmacokinetics of (R)-lansoprazole, the major enantiomer, in CYP2C19 extensive metabolizers (EMs) and on gastroesophageal symptoms in renal transplant recipients receiving tacrolimus. MATERIALS: 24 recipients who were CYP2C19 EMs were studied. METHODS: Oral administration of 30 mg lansoprazole was started 2 days before transplantation. On Day 2 before and Day 28 after transplantation, the plasma concentrations of (R)-lansoprazole and tacrolimus were measured. RESULTS: Pretransplantation, there were no significant differences in the pharmacokinetic parameters of (R)-lansoprazole between the 3 ABCBI C3435T genotypes. However, after renal transplantation, the peak plasma concentration (Cma ) and area under the plasma concentration-time curve (AUCO-24) of (R)-lansoprazole in patients with the ABCB1 C3435T C allele significantly increased, but not in patients with the TT genotype. These pharmacokinetic variations in (R)-lansoprazole did not influence the AUC of tacrolimus. There were no significant differences in the frequency of gastroesophageal symptoms among the three ABCB] C3435Tgenotypes. CONCLUSIONS: (R)-lansoprazole concentrations significantly increased in CYP2C19 extensive metabolizers with the ABCB1 C3435T C allele, but not TT genotype, after renal transplantation. However, the clinical relevance of this observation may be minor because these pharmacogenetic changes were not associated with the occurrence of gastroesophageal complications.

Comparison of enantioselective disposition of rabeprazole versus lansoprazole in renal-transplant recipients who are CYP2C19 extensive metabolizers.

The purpose of this study was to investigate the comparative pharmacokinetics of rabeprazole and lansoprazole enantiomers in renal-transplant recipients on tacrolimus who were CYP2C19 extensive metabolizers. Sixteen Japanese patients were randomly assigned after renal transplantation to receive repeated doses of one of the following two regimens for 28 days; tacrolimus, mycophenolate mofetil and prednisolone together with either 20mg of racemic rabeprazole (n=8) or 30 mg of racemic lansoprazole (n=8). The mean Cmax and AUC0-24 of (R)-lansoprazole compared to (S)-lansoprazole in renal transplant recipients were 12-fold (954+/-522 vs. 167+/-137 ngml(-1), respectively) and 6.9-fold (4787+/-3454 vs. 451+/-354 nghml(-1), respectively) greater, and its elimination half-life was 2.1-fold (2.3+/-1.0 vs. 1.2+/-0.6h, respectively) longer. In contrast, although the elimination half-life of (R)-rabeprazole was significantly longer than that of the (S)-enantiomer (2.1+/-0.5 vs. 1.3+/-0.9h, respectively; P<0.05), there was no difference in Cmax between the (R)- and (S)-enantiomer (186+/-40 vs. 200+/-92 ngml(-1), respectively). In conclusion, in renal-transplant recipients who are CYP2C19 extensive metabolizers, there is less stereoselective difference in the pharmacokinetic disposition between the (R)- and (S)-enantiomers of rabeprazole than those of lansoprazole.

Application of sweet potato fiber to skin wound in rat.

In order to introduce a suitable drug mixing base or covering for burns or decubital wounds, the usefulness of fiber extracted from the sweet potato was investigated. The healing effect of the fiber was evaluated by examining the extent of reduction in the size of wounds and changes in the quality of wounds in rats. In contrast to the control, the use of the fiber alone as a wound covering material reduced wounded areas by 21.0% at postoperative day 9, 19.5% at day 11, and 18.7% at day 13, and resulted in an obvious increase in the rats' weight. The number of days required for healing in all treated rats was 19 for the fiber groups and over 21 d for the control. In vitro, the fiber indicated excellent absorptive ability for serum and good adhesive ability for a number of proteins. This result suggested that the fiber has favorable properties for healing wounds which contain large amounts of exudate. Our macroscopic findings also indicated that the fiber protected wounds from dryness. These results suggested that sweet potato fiber could be use as a covering material in combination with drugs in skin wound therapy.

Renin-sodium profile in experimental nephrosis induced by puromycin aminonucleoside.

The roles of the renin-angiotensin system (RAS) and aldosterone in the pathogenesis of nephrotic syndrome were investigated with rats following subcutaneous injections of puromycin aminonucleoside (PAN) for 7 d. Prominent reduction in plasma renin activity (PRA) was observed at day-15 after the initial treatment with PAN preceded by the onset of the nephrosis and there was no significant difference in plasma aldosterone concentration (PAC) between the nephrosis and normal control groups despite the higher levels obtained in the nephrosis animals. Although we could not elucidate the precise mechanism of reduction in PRA, it was suggested that neither the RAS nor aldosterone secretion played a primary role in the pathogenesis of the nephrosis. PAN-induced nephrosis is interesting in studying the pathophysiological mechanism of the lowered activity of plasma renin in some patients with nephrotic syndrome.

Effect of methylprednisolone and "pulse" therapy with methylprednisolone sodium succinate on autologous immune complex nephritis in rats.

Autologous immune complex (AIC) nephritis was induced in rats with a single foot-pad injection of renal tubular epithelial antigen suspended in complete Freund's adjuvant. It was suggested by gel filtration of serum on Sephadex G-200 column that increase in the concentration of macroglobulins was the first alteration reflected on the serum proteins after immunization; the concentration of macroglobulins increased while the concentrations of albumin and gamma-globulin still remained in the normal range. The effect of 6 alpha-methylprednisolone sodium succinate (MP-S), 6 alpha-methylprednisolone (MP) and cyclophosphamide on the AIC nephritis in rats was studied. "Pulse" therapy, that is, an intraperitoneal administration of a large dose (26.5 mg/kg) of MP-S for 3 successive days a week and followed by an intermission for 4 days a week was started from the week of immunization with renal tubular epithelial antigen and continued for 8 weeks, resulting in the retardation of the AIC nephritis induction associated with a partial suppression of the development of proteinuria. Treatment with MP (4 mg/kg) or cyclophosphamide (10 mg/kg) every other day from the week of immunization for 8 weeks partially retarded or completely suppressed the AIC nephritis induction, respectively. On the other hand, the MP-S "pulse" therapy and the MP treatment of rats suffering from the already established AIC nephritis resulted in no apparent improvement of the disease.