.

5536744133

Lansoprazole

Rabeprazole

Mycophenolic Acid 1

antiulcer

mycophenolic Acid (MPA) active
metabolite mycophenolate mofetil (MMF)
MPA Proton
pump inhibitors (PPIs)

MMF lansoprazole rabeprazole

polymorphism CYP2C19 multidrug resistant
(MDR)1 C3435T
1
Restrospective
61
3

MMF tacrolimus combination
immunosuppressive therapy
lansoprazole 30 mg
(n=22)
rabeprazole 10 mg (n=17)
PPI
(n=22) 1
MPA HPLC dose-
unadjusted dose-adjusted Cmax MPA

lansoprazole 30 mg
PPI (11.8 vs.
17.8 mg/mL, P = 0.0197, 22.6 vs. 33.1 ng/mL/mg MMF, P =
0.0222 ) CYP2C19 *1/*2+*1/*3 MDR1
 . 5536744133

C3435T CC genotype dose-adjusted AUC0-12 MPA

lansoprazole 30 mg

rabeprazole 10 mg
PPI
MPA
lansoprazole 30
mg
rabeprazole 10 mg


lansoprazole 30 mg
CYP2C19 *1/*2+*1/*3 (intermediate metabolizer) MDR1
C3435T CC genotype elution hydrolysis
MMF
lansoprazole 30 mg CYP2C19 *2
allele *3 allele MDR1 C3435T CC genotype
MPA maintenance stage

MPA
pharmacokinetics

(Introduction)

Mycophenolate mofetil (MMF) antimetabolites

(immunosuppressant)

MMF prodrug
esterase mycophenolic Acid
(MPA) active metabolite MMF
MPA

MPA


MPA
cyclosporin, corticosteroids, rifampicin, sevelamer, calcium
polycarbophil, acyclovir, norfloxacin, metro-nidazole Maalox
(antacid)
antacid MPA AUC
 . 5536744133

Cmax MPA
antacid 15%
37% MPA
MPA antacid
elution
hydrolysis MMF
(Peptic ulcer disease)




gastritis, gastric ulcer, duodenal ulcer, duodenitis, esophagitis
esophageal ulcer

early stage maintenance stage

antiulcer

Lansoprazole rabeprazole proton pump

inhibitors (PPIs)

H + / K + -ATPase gastric parietal cells

PPIs


tacrolimus
MMF tacrolimus
PPIs
MPA PPIs

Lansoprazole cytochrome P450
(CYP) 2 CYP2C19 CYP3A
rabeprazole rabeprazole-thioether

CYP2C19 CYP3A4
lansoprazole P-glycoprotein rabeprazole
 . 5536744133

P-glycoprotein

lansoprazole extensive metabolizers
allele CYP2C19 multidrug (MDR) 1 allele
C3435T C genotypes TT

lansoprazole
genetic polymorphism
CYP2C19 MDR1 C3435T

MPA
lansoprazole
rabeprazole genetic polymorphism
CYP2C19 MDR1 C3435T
1

(materials and methods)

(Patients and Protocols)

61

1

(1)

MMF, Tacrolimus
corticosteroids maintenance stage
(2)

(3)
(4) (5)
gastrokinetic



Akita
(inform consent)
 . 5536744133

1 Clinical charecteristics

61 3

MMF, tacrolimus, corticosteroid
immunosuppressive therapy lansoprazole 30
mg (n = 22) rabeprazole 10 mg (n = 17)
PPIs
6 (n = 22)

MMF tacrolimus 12
(09:00 . 21:00 .) MMF
1.5 2 g/day
(
) leukopenia 6 ;
MMF 0.5 2
 . 5536744133

1
MMF
1
leukopenia Trough level
tacrolimus 3-8 ng/mL 1
Prednisolone 5 -10 mg/day
lansoprazole rabeprazole
07:30
6 22 61
PPIs 6


PPIs

( 1,700-2,400
kcal; 70-90 g; 40-50 g; 1,600-2,000 ml)
07:00 . 12:30 . 18:00 .
PPI 07:30 .
1, 2, 3, 4, 6, 9 12

MMF

(Genotyping)

DNA QIAmp Blood Kit (Qiagen,

Hilden, Germany) -80
Genotyping
CYP2C19 wild-type mutant alleles 2 alleles
CYP2C19*2 exon 5 CYP2C19*3 exon 4
polymerase chain reactionrestriction fragment length
 . 5536744133

polymorphism (PCR-RFLP) Genotyping

C T alleles exon 26 MDR1 (C3435T)
PCR-RFLP Cascorbi

HPLC System
MPA High liquid
chromatography (HPLC) lower limit MPA
0.05 ug/mL

(between-day & between-run coefficients of
variation) MPA 9.6% 9.3%
extraction recovery MPA 97.6%
0.5-50 ug/ml HPLC
lansoprazole rabeprazole peak
PPIs 0.5 ug/mL

naproxen internal standard

naproxen

naproxen

(Pharmacokinetic
Analysis)
MPA non-
compartmental method WinNonlin (Pharsight,
Mountain View, CA, 4.0.1) area under the observed
plasma concentration-time curve (AUC)
linear trapezoidal rule (Cmax)
peak (tmax)
 . 5536744133

MMF
MMF
steady state (CL/F)

(Statistical Analysis)

mean SD

MPA 3
PPIs
PPIs

Genotype Mann-Whitney U-
test (SAS Institute, Cary, NC, version 5.0) P-value
0.05

(Results)

, ,
tacrolimus 3
1 ( 1)
MPA

lansoprazole rabeprazole 2
MMF single dose

PPI

lansoprazole dose-adjusted AUC0-6, dose-
unadjusted Cmax, dose-adjusted Cmax tmax MPA
lansoprazole

PPIs
dose-unadjusted trough, dose-adjusted trough (C 0)
AUC0-12 MPA
lansoprazole
 . 5536744133

MPA

lansoprazole
PPI

2 pharmacokinetic parameters MPA

PPI

PPI 1

MMF single dose 1

rabeprazole

lansoprazole PPI
dose-adjusted pharmacokinetic parameters MPA

rabeprazole, lansoprazole

PPI dose-adjusted Cmax trough concentration
MPA
rabeprazole
 . 5536744133

lansoprazole dose-adjusted

MPA 3
dose-adjusted plasma concentration-time
profile MPA 3
1
dose-adjusted plasma concentration MPA
lansoprazole ( 3
MMF)

rabeprazole PPI
dose-adjusted plasma concentration MPA

rabeprazole 6 12
MMF
CYP2C19 *1/*2 + *1/*3
dose-adjusted Cmax, C0, AUC0-12 MPA

lansoprazole

rabeprazole PPI
( 3) dose-adjusted AUC0-12 MPA

lansoprazole
CYP2C19 *1/*2 + *1/*3 genotype

CYP2C19 *1/*1
dose-adjusted AUC0-12 MPA
CYP2C19 *1/*1 3
CYP2C19 *2/*2 + *2/*3 + *3/*3

MDR1 C3435T CC genotype
dose-adjusted Cmax, C0, AUC0-12 MPA

lansoprazole
 . 5536744133

rabeprazole
PPI ( 3)
dose-adjusted AUC0-12 MPA

MDR1 C3435 T allele
3
dose-adjusted AUC0-12 MPA
lansoprazole
MDR1 C3435T CC genotype
T allele ( 3)
MPA CYP2C19
*1/*1 *1/*2 + *1/*3 MDR1 C3435T 2
4
CYP2C19 *1/*1 MDR1
C3435T CT + TT dose-
adjusted AUC0-12 Cmax MPA

lansoprazole
PPI

CYP2C19 *1/*2 + *1/*3 MDR1 C3435T CC

AUC0-12 Cmax MPA

lansoprazole
PPI

1 Mycophenolate mofetil (MMF) dose-adjusted blood

concentration-time profiles mycophenolic acid (MPA)

3 61
1
PPI ( 22 )

lansoprazole 30 mg ( 22 )

 . 5536744133

rabeprazole 10 mg ( 17)

(Discussion)

lansoprazole
(30 mg) dose-unadjusted dose-
adjusted Cmax dose-adjusted AUC0-6 MPA
MPA lansoprazole 30 mg

MPA rabeprazole 10 mg
MPA
lansoprazole
CYP2C19 *1/*2 + *1/*3
MDR1 C3435T CC genotypes
lansoprazole

 . 5536744133

CYP2C19 MDR1 C3435T polymorphism

CYP2C19
rabeprazole
lansoprazole polymorphism MDR1 C3435T
ABCB1 mRNA

C allele TT
genotype lansoprazole
CYP2C19 heterozygous
intermediate metabolizers (IMs) (CYP2C19 *1/*2 + *1/*3)
MDR1 C3435T CC
homozygous extensive metabolizers (EMs) (CYP2C19 *1/*1)
MDR1 C3435T CT + TT

lansoprazole rabeprazole


lansoprazole CYP2C19
IMs MDR1 C3435T CC genotypes (
lansoprazole ) elution

hydrolysis MMF MPA
CYP2C9 poor metabolizer (PM)
lansoprazole dose-adjusted AUC0-12
MPA PM
lansoprazole

PPI
CYP2C19 PM

CYP2C19 *1/*2 + *1/*3
controlled trial
PMs IMs

 . 5536744133

retrospective
MMF single dose 1

lansoprazole

rabeprazole
PPI
dose-adjusted pharmacokinetic parameters MPA
3
pharmacokinetic parameters MPA
rabeprazole
PPI

labeprazole (30mg) rabeprazole (10mg)
7.30 . MMF
12 9.00 . 21.00 .
2
rabeprazole 30 mg/kg K+-ATPase
40% 94%

lansoprazole 30 mg/kg
K+-ATPase 20%
93% 2
lansoprazole rabeprazole


rabeprazole 54% control level 24
rabeprazole 30 mg/kg
lansoprazole 30 mg/kg
20% control level 96
lansoprazole 30 mg

 . 5536744133

lansoprazole
rabeprazole 10 mg
MMF lansoprazole 30
mg MPA

CYP2C19 *2 *3 allele MDR1
C3435T CC genotype MPA
lansoprazole 30 mg Cmax
AUC0-12 MPA
lansoprazole 30 mg
30% 25% control
lansoprazole Cmax MPA tmax MPA
AUC
gastric emptying rate (GER)
transitional time
AUC0-6 MPA

lansoprazole
AUC6-12 ( 1 2) lansoprazole GER

MPA GER pH
lansoprazole MMF catabolite
lansoprazole 30 mg
MPA


antacid pH
lansoprazole

MPA
 . 5536744133

MPA fist pass
lansoprazole MPA
enterohepatic circulation lansoprazole
lansoprazole MMF
lansoprazole
MMF


lansoprazole 30 mg rabeprazole
CYP2C19 *1/*2 + *1/*3 MDR1 C3435T CC
genotypes MPA

3 pharmacokinetic parameters MPA 1

PPI
CYP2C9 MDR1 C3435T genotype
 . 5536744133

4 pharmacokinetic parameters MPA 1

PPI
CYP2C9 MDR1 C3435T genotype

(Conclusion)

PPIs MMF
crossover study
retrospective MPA

lansoprazole 30 mg rabeprazole 10 mg

CYP2C19 *2 *3 allele
MDR1 C3435T CC MMF lansoprazole 30 mg
MPA

MPA lansoprazole
30 mg

hydrolysis
MMF MPA MPA
lansoprazole 30 mg
 . 5536744133

CYP2C19 *2 *3 allele MDR1 C3435T CC

MPA maintenance stage