title: No significant effect of ABCB1 haplotypes on the pharmacokinetics of fluvastatin, pravastatin, lovastatin, and rosuvastatin.
abstract: OBJECTIVE
  This study aimed to investigate possible effects of ABCB1 genotype on fluvastatin, pravastatin, lovastatin, and rosuvastatin pharmacokinetics.
  
  
  METHODS
  In a fixed-order crossover study, 10 healthy volunteers with the ABCB1 c.1236C/C-c.2677G/G-c.3435C/C (CGC/CGC) genotype and 10 with the c.1236T/T-c.2677T/T-c.3435T/T (TTT/TTT) genotype ingested a single 20-mg dose of fluvastatin, pravastatin, lovastatin, and rosuvastatin. Plasma fluvastatin, pravastatin, and lovastatin concentrations were measured up to 12 h and plasma and urine rosuvastatin concentrations up to 48 and 24 h, respectively.
  
  
  RESULTS
  The ABCB1 genotype had no significant effect on the pharmacokinetics of any of the investigated statins. The geometric mean ratio (95% confidence interval) of the area under the plasma concentration-time curve from 0 h to infinity (AUC(0-infinity)) in participants with the TTT/TTT genotype to that in those with the CGC/CGC genotype was 0.96 (0.77, 1.20; P= 0.737) for fluvastatin, 0.92 (0.53, 1.62; P= 0.772) for pravastatin, 0.83 (0.36, 1.90; P= 0.644) for lovastatin, 1.25 (0.72, 2.17; P= 0.400) for lovastatin acid, and 1.10 (0.73, 1.65; P= 0.626) for rosuvastatin. The AUC(0-infinity) of lovastatin acid correlated significantly with that of rosuvastatin (r= 0.570, P= 0.009), but none of the other AUC(0-infinity) pairs showed a significant correlation.
  
  
  CONCLUSIONS
  These data suggest that the ABCB1 c.1236C-c.2677G-c.3435C and c.1236T-c.2677T-c.3435T haplotypes play no significant role in the interindividual variability in the pharmacokinetics of fluvastatin, pravastatin, lovastatin, and rosuvastatin.
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki FI-00029, Finland.
authors.forename: Jenni E
authors.initials: JE
authors.lastname: Keskitalo
authors.forename: Kaisa J
authors.initials: KJ
authors.lastname: Kurkinen
authors.forename: Mikko
authors.initials: M
authors.lastname: Neuvonen
authors.forename: Janne T
authors.initials: JT
authors.lastname: Backman
authors.forename: Pertti J
authors.initials: PJ
authors.lastname: Neuvonen
authors.forename: Mikko
authors.initials: M
authors.lastname: Niemi
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000378:metabolism; D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D005229:Fatty Acids, Monounsaturated / Q000493:pharmacokinetics*; D005260:Female; D005464:Fluorobenzenes / Q000493:pharmacokinetics*; D000077340:Fluvastatin; D005838:Genotype; D006239:Haplotypes / Q000187:drug effects / Q000235:genetics; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics*; D007211:Indoles / Q000493:pharmacokinetics*; D008148:Lovastatin / Q000493:pharmacokinetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000187:drug effects / Q000235:genetics; D017035:Pravastatin / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000493:pharmacokinetics*; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005229:Fatty Acids, Monounsaturated; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D011743:Pyrimidines; D013449:Sulfonamides; D000077340:Fluvastatin; D000068718:Rosuvastatin Calcium; D008148:Lovastatin; D017035:Pravastatin
references.citation: Trends Pharmacol Sci. 2004 Aug;25(8):423-9
references.pmid: 15276711
references.citation: Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3473-8
references.pmid: 10716719
references.citation: N Engl J Med. 2008 Aug 21;359(8):789-99
references.pmid: 18650507
references.citation: Clin Pharmacol Ther. 2005 Nov;78(5):551-8
references.pmid: 16321621
references.citation: Pharmacogenet Genomics. 2006 Dec;16(12):873-9
references.pmid: 17108811
references.citation: Clin Pharmacol Ther. 2006 Dec;80(6):565-81
references.pmid: 17178259
references.citation: Clin Pharmacol Ther. 2006 Oct;80(4):356-66
references.pmid: 17015053
references.citation: Clin Pharmacol Ther. 2008 Oct;84(4):457-61
references.pmid: 19238649
references.citation: Curr Opin Lipidol. 2007 Aug;18(4):409-14
references.pmid: 17620857
references.citation: Drug Metab Dispos. 2005 Apr;33(4):537-46
references.pmid: 15616150
references.citation: Rapid Commun Mass Spectrom. 1999;13(11):1003-15
references.pmid: 10368976
references.citation: Annu Rev Med. 2006;57:119-37
references.pmid: 16409140
references.citation: Atherosclerosis. 2006 Mar;185(1):97-107
references.pmid: 16002074
references.citation: Science. 2007 Jan 26;315(5811):525-8
references.pmid: 17185560
references.citation: Drug Metab Dispos. 2008 Oct;36(10):2014-23
references.pmid: 18617601
references.citation: Pharmacogenet Genomics. 2008 Feb;18(2):77-90
references.pmid: 18192894
references.citation: Pharm Res. 1999 Mar;16(3):408-14
references.pmid: 10213372
references.citation: Pharmacogenet Genomics. 2008 Apr;18(4):299-305
references.pmid: 18334914
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2002 Jun 5;772(2):219-28
references.pmid: 12007766
references.citation: Clin Pharmacol Ther. 1998 Mar;63(3):332-41
references.pmid: 9542477
references.citation: Gastroenterology. 2006 May;130(6):1793-806
references.pmid: 16697742
references.citation: J Pharm Biomed Anal. 2000 Oct;23(5):851-66
references.pmid: 11022911
references.citation: Pharmacogenomics. 2008 Nov;9(11):1695-709
references.pmid: 19018724
references.citation: N Engl J Med. 2008 Aug 21;359(8):856-8
references.pmid: 18650508
references.citation: Eur J Clin Pharmacol. 2006 Jun;62(6):409-15
references.pmid: 16758257
references.citation: Br J Clin Pharmacol. 2008 Sep;66(3):405-10
references.pmid: 18782143
references.citation: J Biol Chem. 1999 Dec 24;274(52):37161-8
references.pmid: 10601278
references.citation: Pharmacogenetics. 2004 Aug;14(8):523-5
references.pmid: 15284534
references.citation: Br J Clin Pharmacol. 1998 Jul;46(1):49-53
references.pmid: 9690949
references.citation: J Pharmacol Exp Ther. 2005 Sep;314(3):1059-67
references.pmid: 15901800
references.citation: Clin Pharmacol Ther. 2003 Apr;73(4):322-9
references.pmid: 12709722
references.citation: Am J Cardiol. 2004 Apr 15;93(8):1046-50
references.pmid: 15081455
references.citation: J Pharm Biomed Anal. 2008 Mar 13;46(4):771-9
references.pmid: 18201852
references.citation: J Mass Spectrom. 2000 Sep;35(9):1133-43
references.pmid: 11006608