ABCMdb

PMID: 17906856

Miura M, Satoh S, Inoue K, Kagaya H, Saito M, Inoue T, Suzuki T, Habuchi T
Influence of SLCO1B1, 1B3, 2B1 and ABCC2 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients.
Eur J Clin Pharmacol. 2007 Dec;63(12):1161-9. Epub 2007 Sep 29., [PubMed]

Sentences

No. Mutations Sentence Comment

3 ABCC2 p.Gly699Ala ABCC2 p.Gly699Ala Results The dose-adjusted area under the cuve (AUC)6-12 of MPA, an estimate of enterohepatic recirculation, was greater in SLCO1B3 T334G GG (or G699A AA) carriers than in TT carriers (or G699A GG) (40 vs. 25 ng·h/mL per milligram, respectively, P=0.0497). Login to comment 6 ABCC2 p.Gly699Ala ABCC2 p.Gly699Ala Conclusions MPA excretion into bile in patients with SLCO1B3 T334G GG (or G699A AA) was higher than in those with T334G TT (or G699A GG), probably resulting in a higher AUC6-12 value of MPA. Login to comment 36 ABCC2 p.Gly699Ala The SLCO1B3 G699A A allele increases uptake transport activity in vitro [20]. Login to comment 54 ABCC2 p.Gly699Ala ABCC2 p.Gly699Ala ABCC2 p.Gly699Ala Diagnosis of gastrointestinal side effects of MMF MMF-related gastrointestinal side effects, such as diarrhea, nausea, vomiting, or abdominal pain, were defined by the absence of any other demonstrable etiology and improve- Table 2 Pharmacokinetic parameters of mycophenolic acid (MPA) and tacrolimus in the SLCO1B1 genotype groups Genotype group *1a/*1a *1a/*1b *1b/*1b *1a/*15 *1b/*15 *15/*15 ANOVA P Patient numbers (%) 6 (7) 35 (40) 17 (20) 8 (12) 19 (9) 2 (2) Patients with diarrhea (%) 1 (17) 10 (29) 4 (24) 1 (13) 8 (42) 0 Prednisolone (mg/kg) 0.20±0.04 0.20±0.06 0.19±0.04 0.16±0.04 0.20±0.03 0.21±0.08 0.4825 MPA MMF single dose (mg) 750±158 786±162 838±152 875±189 794±159 1000±0 0.2953 Dose-adjusted Cmax (μg/mL/g) 15.2±5.6 18.0±5.5 15.1±7.4 19.1±7.5 19.5±9.9 6.7±1.7 0.1175 Dose-adjusted C0 (μg/mL/g) 6.0±2.2 5.4±3.6 4.2±2.7 4.8±3.0 5.4±3.0 3.7±1.0 0.7278 CL/F (L/hr/kg) 0.16±0.05 0.16±0.06 0.23±0.27 0.12±0.02 0.15±0.07 0.34±0.03 0.1413 AUC0-12/D (μg·h/mL/g) 103±38 95±31 89±51 99±20 106±45 37±2 0.2543 AUC0-6/D (μg·h/mL/g) 64±27 59±17 57±36 63±17 66±29 21±1 0.2735 AUC6-12/D (μg·h/mL/g) 40±12 36±28 32±19 36±11 40±22 16±0.2 0.7484 AUC6-12/AUC0-12 (%) 40±6.9 35±13 36±13 36±9 37±11 44±1 0.8775 Tacrolimus Single dose (mg/kg) 0.08±0.02 0.10±0.05 0.09±0.04 0.09±0.04 0.10±0.05 0.15±0 0.4080 Dose-adjusted C0 (μg/ml/mg/kg) 0.16±0.06 0.15±0.08 0.15±0.07 0.19±0.11 0.13±0.06 0.08±0.01 0.3492 AUC0-12/D (μg·h/ml/mg/kg) 2.67±0.90 2.34±1.07 2.38±1.05 2.63±1.49 1.94±0.82 1.51±0.15 0.4080 Values are shown as the mean ± SD. There were no significant differences in MPA pharmacokinetics between SLCO1B1*1a/*1a and *1b/*1b, *1a/*1a and *1a/*15, and *1b/*1b and *1b/*15 Cmax maximum plasma concentration, CL/F apparent oral clearance, AUC0-12, AUC0-6, and AUC6-12, area under the plasma concentration-time curve from 0 to 12 h, 0 to 6 h, and 6 to 12 h, respectively, D single dose, ANOVA analysis of variance Table 3 Pharmacokinetic parameters of mycophenolic acid (MPA) and tacrolimus in the SLCO1B3 T334G and G699A genotype groups Genotype group T334G T/T T/G G/G ANOVA P values G699A G/G G/A A/A Patient numbers (%) 10 (12) 40 (45) 37 (43) Patients with diarrhea (%) 4 (40) 8 (20) 12 (32) Prednisolone (mg/kg) 0.19±0.03 0.19±0.05 0.20±0.04 0.7317 MPA Single dose (mg) 750±189 827±142 804±178 0.4315 Dose-adjusted Cmax (μg/mL/g) 19.6±12.6 16.3±6.4 17.9±6.6 0.4107 Dose-adjusted C0 (μg/mL/g) 4.5±1.4 4.8±3.2 5.6±3.3 0.4028 CL/F (L/h/kg) 0.18±0.07 0.16±0.07 0.18±0.19 0.8127 AUC0-12/D (μg·h/mL/g) 85±37 90±35 104±43 0.2333 AUC0-6/D (μg·h/mL/g) 60±29 57±22 64±28 0.4921 AUC6-12/D (μg·h/mL/g) 25±10 34±17 40±28* 0.1684 AUC6-12/AUC0-12 (%) 31±8 37±9 37±14 0.3615 Tacrolimus Single dose (mg/kg) 0.09±0.03 0.09±0.04 0.10±0.06 0.4414 Dose-adjusted C0 (μg/ml/mg/kg) 0.16±0.09 0.15±0.08 0.14±0.06 0.6178 AUC0-12/D (μg·h/ml/mg/kg) 2.42±0.90 2.31±1.13 2.24±1.01 0.8875 Values are shown as the mean ± SD Cmax maximum plasma concentration, CL/F apparent oral clearance, AUC0-12, AUC0-6, and AUC6-12 area under the plasma concentration-time curve from 0 to 12 h, 0 to 6 h, and 6 to 12 h, respectively, D single dose, ANOVA analysis of variance *P<0.05 compared with the SLCO1B3 T334G TT (or OATP1B3 G699A GG) ment or resolution of symptoms by reduction of the dose of MMF alone. Login to comment 75 ABCC2 p.Gly699Ala Results Association of SLCO1B1 polymorphisms with MPA pharmacokinetics The SLCO1B1*1a/*1a, *1a/*1b, *1b/*1b, *1a/*15, *1b/ *15, and *15/*15 genotypes were detected in 6 (7%), 35 0 5 10 15 20 MPA plasma concentration (µg/mL) 0 2 4 6 8 10 12 Time (h) 334G/G (699A/A) 334T/G (699G/A) 334T/T (699G/G) Fig. 1 Mean ± SD of the plasma concentration-time profiles of mycophenolic acid (MPA) in recipients having SLCO1B3 T334G TT genotype (G699A GG) (open circles), TG (GA) (open square), and GG (AA) (solid circles) carriers 0 50 100 150 AUC ( µ g h/mL/g) AUC6-12/D AUC0-6 /D AUC0-12/D 334G/G (699A/A) 334T/G (699G/A) 334T/T (699G/G) Fig. 2 The area under the plasma concentration-time curve from 0 to 12 h (AUC0-12) (open column), the partial AUC from 0 to 6 h (AUC0-6) (gray column), and from 6 to 12 h (AUC6-12) (solid column). Login to comment 81 ABCC2 p.Gly699Ala Association of SLCO1B3 polymorphisms with MPA pharmacokinetics The SLCO1B3 T334G TT, TG, and GG (G699A GG, GA and AA) genotypes were detected in 10 (12%), 40 (45%) and 37 (43%) patients, respectively, and the genotype distribution was in Hardy-Weinberg equilibrium [22]. Login to comment 82 ABCC2 p.Gly699Ala The SLCO1B3 T334G and G699A showed complete linkage disequilibrium (Table 3). Login to comment 86 ABCC2 p.Gly699Ala ABCC2 p.Gly699Ala However, the dose-adjusted AUC6-12 of MPA was significantly greater in SLCO1B3 T334G GG (G699A GG) genotype carriers than in TT (G699A AA) genotype carriers (40 vs. 25 μg·h/ml per gram, P=0.0497) (Fig. 2). Login to comment 97 ABCC2 p.Gly699Ala ABCC2 p.Gly699Ala Table 5 Pharmacokinetic parameters of mycophenolic acid (MPA) and tacrolimus in the ABCC2 C-24T genotype groups Genotype group C/C C/T T/T ANOVA P value CT+T/T P value vs. C/C Patient numbers (%) 47 (53) 37 (42) 4 (5) 41 Patients with diarrhea (%) 13 (28) 11 (30) 0 (0) Prednisolone (mg/kg) 0.20±0.05 0.18±0.03* 0.23±0.08 0.0683 MPA Single dose (mg) 783±174 847±150 750±0 0.1608 838±145 0.1247 Dose-adjusted Cmax (μg/mL/g) 16.9±6.4 18.3±8.4 14.1±6.4 0.4744 17.9±8.3 0.5569 Dose-adjusted C0 (μg/mL/g) 5.0±2.8 5.1±3.2 6.2±5.9 0.7806 5.2±3.4 0.7868 CL/F (L/h/kg) 0.19±0.17 0.16±0.07 0.19±0.07 0.8127 0.16±0.07 0.3656 AUC0-12/D (μg·h/mL/g) 94±37 98±42 85±34 0.7752 97±41 0.7321 AUC0-6/D (μg·h/mL/g) 61±24 60±28 51±20 0.7690 59±27 0.8181 AUC6-12/D (μg·h/mL/g) 34±18 38±28 34±15 0.6640 38±27 0.3940 AUC6-12/AUC0-12 (%) 35±9 37±14 40±5 0.4927 38±14 0.2734 Tacrolimus Single dose (mg/kg) 0.10±0.04 0.09±0.05 0.11±0.05 0.6992 0.09±0.05 0.6473 Dose-adjusted C0 (μg/ml/mg/kg) 0.14±0.08 0.16±0.08 0.11±0.04 0.3699 0.15±0.08 0.5262 AUC0-12/D (μg·h/ml/mg/kg) 2.26±1.03 2.42±1.09 1.46±0.51 0.2114 2.32±1.08 0.7941 Values are shown as the mean ± SD. There were no significant difference in MPA pharmacokinetics between ABCC2 -24C/C and other genotype groups Cmax maximum plasma concentration, CL/F apparent oral clearance, AUC0-12, AUC0-6, and AUC6-12 area under the plasma concentration-time curve from 0 to 12 h, 0 to 6 h, and 6 to 12 h, respectively, D single dose, ANOVA analysis of variance Table 6 Pharmacokinetic parameters of mycophenolic acid (MPA) in the SLCO1B3 T334G (G699A) and ABCC2 C-24T genotype groups Genotype group T334G (G699A) TT (GG) TG (GA) GG (AA) ANOVA P value ABCC2 C-24T C/C C/T+T/T C/C C/T+T/T C/C C/T+T/T C/C C/T+T/T Patient numbers 5 5 21 19 20 17 MPA Single dose (mg) 750±177 750±204 813±160 842±124 763±190 853±155 Dose-adjusted Cmax (μg/mL/g) 15.3±1.7 25.0± 18.7 16.3±6.7 16.4±6.1 18.0±6.7 17.8±6.6 0.5877 0.1711 Dose-adjusted C0 (μg/mL/g) 4.5±1.6 4.5±1.4 5.0±3.1 4.6±3.3 5.2±2.8 6.2±3.8 0.8794 0.3533 CL/F (L/h/kg) 0.18± 0.02 0.18±0.11 0.17± 0.07 0.16± 0.07 0.21± 0.25 0.15±0.06 * 0.7531 0.8215 AUC0-12/D (μg·h/mL/g) 75±18 98±53 89±30 92±39 105±45 102±41 0.1962 0.7655 AUC0-6/D (μg·h/mL/g) 53±12 69±43 54±17 59±26 69±30 58±25 0.1284 0.7558 AUC6-12/D (μg·h/mL/g) 23±8 29±12 34±18 33±17 36±19 45±36 0.3351 0.3481 AUC6-12/AUC0-12 (%) 30±6 33±9 38±10 36±9 34±9 41±18 0.1538 0.3798 Values are shown as the mean ± SD Cmax maximum plasma concentration, CL/F apparent oral clearance, AUC0-12, AUC0-6, and AUC6-12 area under the plasma concentration-time curve from 0 to 12 h, 0 to 6 h, and 6 to 12 h, respectively, D, single dose. Login to comment 99 ABCC2 p.Gly699Ala Combination of SLCO1B3 T334G and ABCC2 C-24T polymorphisms The pharmacokinetic parameters of MPA as they relate to ABCC2 C-24T polymorphisms in the three different SLCO1B3 T334G (G699A) genotype groups are shown in Table 6. Login to comment 103 ABCC2 p.Gly699Ala ABCC2 p.Gly699Ala The SLCO1B3 T334G GG (or G699A AA) genotypes, which are in linkage disequilibrium, increased the dose-adjusted AUC6-12 of MPA compared with those in SLCO1B3 T334G TT (or G699A GG). Login to comment 151 ABCC2 p.Gly699Ala In conclusion, this study showed that the SLCO1B3 T334G (or G699A) polymorphism was associated with the MPA AUC6-12. Login to comment