Naunyn-Schmiedeberg’ s Arch Pharmacol (2006) 373: 45–50 DOI 10.1007/s00210-006-0053-6 ORIGINAL ARTICLE Thomas Gerloff . Melanie Schaefer . Jessica Mwinyi . Andreas Johne . Thomas Sudhop . Dieter Lütjohann . Ivar Roots . Klaus von Bergmann Influence of the SLCO1B1*1b and *5 haplotypes on pravastatin’s cholesterol lowering capabilities and basal sterol serum levels Received: 24 October 2005 / Accepted: 20 February 2006 / Published online: 28 March 2006 # Springer-Verlag 2006 Abstract We previously showed that variant SLCO1B1 haplotype *1b (A388G) accelerates and that *5 (T521C) delays hepatocellular uptake of the HMG-CoA reductase inhibitor pravastatin [Mwinyi et al. (2004): Clin Pharmacol Ther 75:415–421]. In the present study we checked for differential effects of variant SLCO1B1 haplotypes on hepatocellular cholesterol synthesis. We analyzed the serum levels of cholesterol, lathosterol, and campesterol in healthy white males which had been grouped on the basis of their SLCO1B1 haplotype: *1a (n=10), *1b (n=10), and *5 (n=8). The subjects received a single oral dose of 40 mg pravastatin. Cholesterol and lathosterol levels were lower in all subjects following pravastatin intake for up to 24. Median levels 6 h post-dosing of lathosterol decreased in each SLCO1B1 haplotype group in the rank order of *1b (-0.11 mg dl –1 ; min–max: -0.20 to -0.04; p=0.005) > *1a (-0.09 mg dl –1 ; min–max: -0.22 to -0.05; p=0.005) > *5 (-0.07 mg dl –1 ; min–max: -0.17 to -0.05; p=0.012). Lathosterol median-change values were significantly great- er in haplotype *1b than in haplotype *5 individuals (p=0.041, non-adjusted), which was congruent with the extent of mean changes in lathosterol-to-cholesterol ratios, although the latter did not reach statistical significance. Post-treatment serum levels of campesterol were not affected by SLCO1B1 haplotype. Interestingly, sterol basal serum levels tended to be highest in *1b carriers, followed by those in *1a and *5 individuals, with significant differences in lathosterol concentrations be- tween the *1b and *5 (p=0.041, non-adjusted) haplotype group. Our findings suggest an association of SLCO1B1*1b and *5 haplotypes to pravastatin’ s inhibition of the hepatocellular HMG-CoA reductase. Furthermore, SLCO1B1 haplotypes seem to play a role in basal cholesterol homeostasis. Keywords Bile acids . HMG CoA reductase inhibition . Lathosterol . Nuclear receptor . Oxysterols . Pharmacogenetics . SLCO1B1 Introduction The hepatocellular uptake transporter OATP1B1 (SLCO1B1), which is a member of the organic anion transporting polypeptide family, plays an important role in the extraction of a large variety of endogenous compounds, drugs, and other xenobiotics from portal venous blood. The spectrum of OATP1B1 substrates includes bile acids and conjugated steroids (Kullak-Ublick et al. 2001; Tamai et al. 2001), angiotensin inhibitors (Ishizuka et al. 1998), β-lactam antibiotics (Marzolini et al. 2004) and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (Marzolini et al. 2004). Various synonymous and non-synonymous single nucleotide poly- morphisms (SNPs) have been identified within the SLCO1B1 gene (Michalski et al. 2002; Niemi et al. 2004; Nozawa et al. 2002; Tirona et al. 2001). Most of these SNPs have been found to be associated with altered in vitro transport characteristics of the prototypic compounds estrone sulfate and estradiol 17β-D-glucuronide (Tirona et al. 2001). Moreover, several investigating groups have recently demonstrated the in vivo relevance of the SLCO1B1*1b (Val174), *5 (Asp130) and *15 (Asp130Val174) haplotypes on the pharmacokinetics of the HMG-CoA reductase inhibitor pravastatin (Mwinyi et al. 2004; Niemi et al. 2004; Nishizato et al. 2003). Subjects T. Gerloff (*) . M. Schaefer . J. Mwinyi . A. Johne . I. Roots Institute of Clinical Pharmacology, Charité University Medical Center, Humboldt University of Berlin, Schumannstrasse 20/21, 10098 Berlin, Germany e-mail: thomas.gerloff@gmx.de Tel.: +49-30-450525004 Fax: +49-30-450525933 T. Gerloff . M. Schaefer . I. Roots Cenimed GmbH, Center for Individualized Medicine, Clinical Pharmacogenomics, Berlin, Germany T. Sudhop . D. Lütjohann . K. von Bergmann Department of Clinical Pharmacology, University of Bonn, 53105 Bonn, Germany