ABCMdb

ABCC2 p.Gly699Ala

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Publications

PMID: 18695635 [PubMed] Miura M et al: "Influence of drug transporters and UGT polymorphisms on pharmacokinetics of phenolic glucuronide metabolite of mycophenolic acid in Japanese renal transplant recipients."

No. Sentence Comment

14 OATPs, encoded by SLCO genes, mediate the transmembrane transport of a wide range of amphiphilic organic compounds.10 The area under the plasma concentration-time curve (AUC)6-12 of an organic anion MPA, which estimates enterohepatic circulation and recirculation of MPA, was greater in SLCO1B3 T334G GG (or G699A AA) carriers than in TT carriers (or G699A GG).11 On the other hand, MRP2/ABCC2 is expressed at the hepatocyte apical membrane, the proximal renal tubular cell luminal membrane, and intestinal epithelial cells.12 Naesens et al13 reported that ABCC2 C-24T polymorphisms are associated with MPA oral clearance. Login to comment

PMID: 18762709 [PubMed] Maeda K et al: "Impact of genetic polymorphisms of transporters on the pharmacokinetic, pharmacodynamic and toxicological properties of anionic drugs."

No. Sentence Comment

124 T334G (Ser112Ala) and G669A (Met233Ile) are observed frequently in OATP1B3 gene in all ethnic populations, and these two SNPs are tightly linked to each other.23) T334G mutation in OATP1B3 was reported to increase in the plasma AUC (6-12 hr after oral administration) of mycophenolic acid, suggesting that this mutation decreased the transport function of OATP1B3.62) However, the 1/Tmax value in the erythromycin breath test was significantly higher in subjects with T334G, indicating that T334G accelerates the metabolism of erythromycin, which is inconsistent with the clinical study mentioned above.63) On the other hand, T334G and G699A in OATP1B3 did not affect the pharmacokinetics of paclitaxel, docetaxel, telmisartan, which are substrates of OATP1B3.64-66) Very recently, Kiyotani et al. have shown that SNPs in the non-coding region of OATP1B3 and MRP2 are associated with the frequency of docetaxel-induced severe neutropenia in cancer patients with the use of a data-mining approach from ``Biobank Japan'' (http://www.biobankjp.org/), which possesses genome and serum samples from more than 200,000 patients with clinical information.67) This novel approach enables genome-wide searches to find the unknown causal genes for the modification of drug responses. Login to comment

PMID: 20103563 [PubMed] Klaassen CD et al: "Xenobiotic, bile acid, and cholesterol transporters: function and regulation."

No. Sentence Comment

6427 Nucleotide Change Amino Acid Change In Vitro Function Protein Expression/Localization SLCO1A2 OATP1A2 T38C I13T 1↔ Normal A382T N128Y ↔ N.D. A404T N135I 2↔ N.D. C502T R168C 2 N.D. A516C E172D 2 Intracellular G559A A187T 2 Normal A833- Asn278STOP 2 N.D. C2003G T668S ↔ Intracellular SLCO1B1 OATP1B1 T217C F73L 2 Intracellular T245C V82A 2 Intracellular A388G N130D 2↔ Normal A452G N151S N.D. N.D. C463A P155T ↔ Normal A467G E156G 2 Normal T521C V174A 2 Intracellular/normal T578G L193R 2 Intracellular C1007G P336R N.D. N.D. T1058C I353T 2 Intracellular A1294G N432D 2↔ Normal A1385G D462G ↔ Normal G1454T C485F N.D. N.D. G1463C G488A 2 Intracellular T1628G L543W N.D. N.D. A1964G D655G 2↔ Normal A2000G E667G 2↔ Normal SLCO1B3 OATP1B3 T334G S112A 1↔ Normal G699A M233I ↔ Normal G1564T G522C 2↔ Reduced G1748A G583E 2↔ Reduced 2, reduced function; 1, increased function; ↔, no change in function; N.D. not determined. ions. Login to comment
6426 Nucleotide Change Amino Acid Change In Vitro Function Protein Expression/Localization SLCO1A2 OATP1A2 T38C I13T 1࢒ Normal A382T N128Y ࢒ N.D. A404T N135I 2࢒ N.D. C502T R168C 2 N.D. A516C E172D 2 Intracellular G559A A187T 2 Normal A833- Asn278STOP 2 N.D. C2003G T668S ࢒ Intracellular SLCO1B1 OATP1B1 T217C F73L 2 Intracellular T245C V82A 2 Intracellular A388G N130D 2࢒ Normal A452G N151S N.D. N.D. C463A P155T ࢒ Normal A467G E156G 2 Normal T521C V174A 2 Intracellular/normal T578G L193R 2 Intracellular C1007G P336R N.D. N.D. T1058C I353T 2 Intracellular A1294G N432D 2࢒ Normal A1385G D462G ࢒ Normal G1454T C485F N.D. N.D. G1463C G488A 2 Intracellular T1628G L543W N.D. N.D. A1964G D655G 2࢒ Normal A2000G E667G 2࢒ Normal SLCO1B3 OATP1B3 T334G S112A 1࢒ Normal G699A M233I ࢒ Normal G1564T G522C 2࢒ Reduced G1748A G583E 2࢒ Reduced 2, reduced function; 1, increased function; ࢒, no change in function; N.D. not determined. ions. Login to comment

PMID: 19545654 [PubMed] Rosso Felipe C et al: "Clinical impact of polymorphisms of transport proteins and enzymes involved in the metabolism of immunosuppressive drugs."

No. Sentence Comment

198 In one study including 87 Japanese kidney transplant recipients, carriers of the SNP (T334G or G699A) of one OATP transport member (SLCO1 B3), which have increased uptake transport activity, showed higher dose-adjusted MPA exposure compared with wild-type carriers. Login to comment

PMID: 21572388 [PubMed] Miura M et al: "Monitoring of mycophenolic acid predose concentrations in the maintenance phase more than one year after renal transplantation."

No. Sentence Comment

34 procedure as previously described.16,17 UGT1A9 I399C/T (relative to the end of UGT1A9 exon 1) was genotyped by direct sequencing with a PCR procedure as previously described.18 A genotyping procedure to identify the SLCO1B1 1a, 1b, and *15 alleles was performed using the PCR-RFLP method of Nozawa et al19 Genotyping procedures identifying each allele of the SLCO1B3 gene (T334G and G699A) used the PCR-RFLP method described by Tsujimoto et al20 Genotyping procedures identifying the C and T alleles in exon 1 of ABCC2 (C-24T) were performed by combining 2 PCR-RFLP methods described by Rau et al21 The ABCG2 C421A polymorphism was genotyped by the PCR-RFLP method of Kobayashi et al22 All the frequencies for the different analyzed loci were in Hardy-Weinberg equilibrium. Login to comment

PMID: 17906856 [PubMed] Miura M et al: "Influence of SLCO1B1, 1B3, 2B1 and ABCC2 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients."

No. Sentence Comment

3 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 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 The SLCO1B3 G699A A allele increases uptake transport activity in vitro [20]. Login to comment
54 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 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 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 The SLCO1B3 T334G and G699A showed complete linkage disequilibrium (Table 3). Login to comment
86 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 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 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 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 In conclusion, this study showed that the SLCO1B3 T334G (or G699A) polymorphism was associated with the MPA AUC6-12. Login to comment

PMID: 21878834 [PubMed] Bouamar R et al: "Mycophenolic acid-related diarrhea is not associated with polymorphisms in SLCO1B nor with ABCB1 in renal transplant recipients."

No. Sentence Comment

165 For example, recently, Liu Table 5 Dose-adjusted mycophenolic acid-area under the curve in patients using cyclosporine as comedication according to ABCB1 and SLCO genotypes Dose-adjusted MPA-AUC (mg.h/l) ± SD n (%) Day 3 Day 10 Month 1 Month 3 Month 6 Month 12 ABCB1 1236C > T CC 55 (33) 31 ± 10 29 ± 13 34 ± 12 41 ± 15 48 ± 14 46 ± 16 CT 84 (51) 31 ± 10 31 ± 12 34 ± 17 44 ± 23 49 ± 24 48 ± 21 TT 27 (16) 36 ± 16 30 ± 10 32 ± 11 41 ± 16 46 ± 14 45 ± 16 2677G > T/A GG 53 (31) 32 ± 10 30 ± 14 35 ± 13 43 ± 17 50 ± 15 45 ± 16 GT/TT 111 (65) 32 ± 12 31 ± 12 33 ± 16 43 ± 21 48 ± 21 48 ± 19 GA 6 (4) 30 ± 5 23 ± 3 27 ± 9 25 ± 10 35 ± 5 49 ± 10 3435C > T CC 36 (22) 32 ± 8 28 ± 9 32 ± 10 41 ± 15 48 ± 15 43 ± 16 CT 90 (54) 31 ± 11 30 ± 12 35 ± 17 43 ± 23 48 ± 22 47 ± 18 TT 40 (24) 33 ± 14 33 ± 14 33 ± 11 43 ± 16 48 ± 17 49 ± 20 SLCO1B1 T521C CC 8 (5) 38 ± 15 29 ± 8 37 ± 24 47 ± 19 54 ± 10 45 ± 13 TC 49 (29) 31 ± 12 29 ± 12 33 ± 19 43 ± 29 50 ± 25 50 ± 26 TT 110 (66) 32 ± 10 31 ± 13 34 ± 12 42 ± 15 47 ± 17 47 ± 17 A388G AA 48 (29) 30 ± 9 27 ± 8 30 ± 12 36 ± 12 42 ± 15 45 ± 16 AG 67 (40) 33 ± 13 32 ± 14 35 ± 17 44 ± 17 49 ± 16 48 ± 17 GG 46 (27) 32 ± 9 32 ± 13 35 ± 15 45 ± 25 51 ± 24 45 ± 20 SLCO1B3 T344G GG 111 (66) 31 ± 10 29 ± 12 33 ± 15 41 ± 17 45 ± 18 49 ± 21 GT 51 (31) 33 ± 13 33 ± 13 36 ± 14 48 ± 26 56 ± 22 46 ± 17 TT 5 (3) 37 ± 14 33 ± 8 26 ± 9 39 ± 17 52 ± 5 43 ± 14 G699A AA 110 (66) 31 ± 10 29 ± 12 33 ± 15 41 ± 17 45 ± 18a 48 ± 19 GA 50 (30) 33 ± 14 33 ± 13 37 ± 14 49 ± 26 56 ± 22 46 ± 17 GG 5 (3) 37 ± 14 33 ± 8 26 ± 9 39 ± 17 52 ± 5 43 ± 14 MPA-AUC, mycophenolic acid-area under the curve; SD, standard deviation. a Significant (P < 0.05). Login to comment