TY - JOUR
T1 - Effects of organic anion transporting polypeptide 1B1 haplotype on pharmacokinetics of pravastatin, valsartan, and temocapril
AU - Maeda, Kazuya
AU - Ieiri, Ichiro
AU - Yasuda, Kuninobu
AU - Fujino, Akiharu
AU - Fujiwara, Hiroaki
AU - Otsubo, Kenji
AU - Hirano, Masaru
AU - Watanabe, Takao
AU - Kitamura, Yoshiaki
AU - Kusuhara, Hiroyuki
AU - Sugiyama, Yuichi
PY - 2006/5
Y1 - 2006/5
N2 - Objective: Recent reports have shown that genetic polymorphisms in organic anion transporting polypeptide (OATP) 1B1 have an effect on the pharmacokinetics of drugs. However, the impact of OATP1B1*1b alleles, the frequency of which is high in all ethnicities, on the pharmacokinetics of substrate drugs is not known after complete separation of subjects with OATP1B1*1a and *1b. Furthermore, the correlation between the clearances of OATP1B1 substrate drugs in individuals has not been characterized. We investigated the effect of genetic polymorphism of OATP1B1, particularly the *1b allele, on the pharmacokinetics of 3 anionic drugs, pravastatin, valsartan, and temocapril, in Japanese subjects. Methods: Twenty-three healthy Japanese volunteers were enrolled in a 3-period crossover study. In each period, after a single oral administration of pravastatin, valsartan, or temocapril, plasma and urine were collected for up to 24 hours. Results: The area under the plasma concentration-time curve (AUC) of pravastatin in *1b/*1b carriers (47.4 ± 19.9 ng · h/mL) was 65% of that in *1a/*1a carriers (73.2 ± 23.5 ng · h/mL) (P = .049). Carriers of *1b/*15 (38.2 ± 15.9 ng · h/mL) exhibited a 45% lower AUC than *1a/*15 carriers (69.2 ± 23.4 ng · h/mL) (P = .024). In the case of valsartan we observed a similar trend as with pravastatin, although the difference was not statistically significant (9.01 ± 3.33 μg · h/mL for *1b/*1b carriers versus 12.3 ± 4.6 μg · h/mL for *1a/*1a carriers [P = .171] and 6.31 ± 3.64 μg · h/mL for *1b/*15 carriers versus 9.40 ± 4.34 μg · h/mL for *1a/*15 carriers [P = .213]). The AUC of temocapril also showed a similar trend (12.4 ± 4.1 ng · h/mL for *1b/*1b carriers versus 18.5 ± 7.7 ng · h/mL for *1a/*1a carriers [P = .061] and 16.4 ± 5.0 ng · h/mL for *1b/*15 carriers versus 19.0 ± 4.1 ng · h/mL for *1a/*15 carriers [P = .425]), whereas that of temocaprilat (active form of temocapril) was not significantly affected by the haplotype of OATP1B1. Interestingly, the AUC of valsartan and temocapril in each subject was significantly correlated with that of pravastatin (R = 0.630 and 0.602, P < .01). The renal clearance remained unchanged for each haplotype for all drugs. Conclusion: The major clearance mechanism of pravastatin, valsartan, and temocapril appears to be similar, and OATP1B1*1b is one of the determinant factors governing the interindividual variability in the pharmacokinetics of pravastatin and, possibly, valsartan and temocapril.
AB - Objective: Recent reports have shown that genetic polymorphisms in organic anion transporting polypeptide (OATP) 1B1 have an effect on the pharmacokinetics of drugs. However, the impact of OATP1B1*1b alleles, the frequency of which is high in all ethnicities, on the pharmacokinetics of substrate drugs is not known after complete separation of subjects with OATP1B1*1a and *1b. Furthermore, the correlation between the clearances of OATP1B1 substrate drugs in individuals has not been characterized. We investigated the effect of genetic polymorphism of OATP1B1, particularly the *1b allele, on the pharmacokinetics of 3 anionic drugs, pravastatin, valsartan, and temocapril, in Japanese subjects. Methods: Twenty-three healthy Japanese volunteers were enrolled in a 3-period crossover study. In each period, after a single oral administration of pravastatin, valsartan, or temocapril, plasma and urine were collected for up to 24 hours. Results: The area under the plasma concentration-time curve (AUC) of pravastatin in *1b/*1b carriers (47.4 ± 19.9 ng · h/mL) was 65% of that in *1a/*1a carriers (73.2 ± 23.5 ng · h/mL) (P = .049). Carriers of *1b/*15 (38.2 ± 15.9 ng · h/mL) exhibited a 45% lower AUC than *1a/*15 carriers (69.2 ± 23.4 ng · h/mL) (P = .024). In the case of valsartan we observed a similar trend as with pravastatin, although the difference was not statistically significant (9.01 ± 3.33 μg · h/mL for *1b/*1b carriers versus 12.3 ± 4.6 μg · h/mL for *1a/*1a carriers [P = .171] and 6.31 ± 3.64 μg · h/mL for *1b/*15 carriers versus 9.40 ± 4.34 μg · h/mL for *1a/*15 carriers [P = .213]). The AUC of temocapril also showed a similar trend (12.4 ± 4.1 ng · h/mL for *1b/*1b carriers versus 18.5 ± 7.7 ng · h/mL for *1a/*1a carriers [P = .061] and 16.4 ± 5.0 ng · h/mL for *1b/*15 carriers versus 19.0 ± 4.1 ng · h/mL for *1a/*15 carriers [P = .425]), whereas that of temocaprilat (active form of temocapril) was not significantly affected by the haplotype of OATP1B1. Interestingly, the AUC of valsartan and temocapril in each subject was significantly correlated with that of pravastatin (R = 0.630 and 0.602, P < .01). The renal clearance remained unchanged for each haplotype for all drugs. Conclusion: The major clearance mechanism of pravastatin, valsartan, and temocapril appears to be similar, and OATP1B1*1b is one of the determinant factors governing the interindividual variability in the pharmacokinetics of pravastatin and, possibly, valsartan and temocapril.
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U2 - 10.1016/j.clpt.2006.01.011
DO - 10.1016/j.clpt.2006.01.011
M3 - Article
C2 - 16678545
AN - SCOPUS:33646205286
SN - 0009-9236
VL - 79
SP - 427
EP - 439
JO - Clinical Pharmacology and Therapeutics
JF - Clinical Pharmacology and Therapeutics
IS - 5
ER -