PHARMACODYNAMICS CYP3A induction and inhibition by different antiretroviral regimens reflected by changes in plasma 4β-hydroxycholesterol levels F. Josephson & L. Bertilsson & Y. Böttiger & L. Flamholc & M. Gisslén & V. Ormaasen & A. Sönnerborg & U. Diczfalusy Received: 18 January 2008 / Accepted: 26 March 2008 / Published online: 6 May 2008 # Springer-Verlag 2008 Abstract Objective and methods A member of the major human cytochrome P450 superfamily of hemoproteins, CYP3A4/5, converts cholesterol into 4β-hydroxycholesterol. We studied plasma 4β-hydroxycholesterol levels prior to and 4 weeks after initiating antiretroviral therapy that included efavirenz, ritonavir-boosted atazanavir or ritonavir-boosted lopinavir with the aim of exploring the usefulness of plasma 4β- hydroxycholesterol levels as an endogenous biomarker of CYP3A activity. Efavirenz is an inducer of CYP3A, whereas the ritonavir-boosted regimens are net inhibitors of CYP3A. Results In patients treated with efavirenz, the median plasma 4β-hydroxycholesterol level increased by 46 ng/mL (p =0.004; n =11). In contast, patients given ritonavir-boosted atazanavir showed a median decrease in plasma 4β- hydroxycholesterol of -9.4 ng/mL (p =0.0003; n =22), and those given ritonavir-boosted lopinavir showed a median change from baseline of –5.8 ng/mL (p =0.38; n =19). There were significant between-group differences in the effects of antiretroviral treatment on plasma 4β-hydroxycholesterol levels (p <0.0001). Conclusion Changes in plasma 4β-hydroxycholesterol fol- lowing the initiation of efavirenz- or atazanavir/ritonavir- based antiretroviral therapy reflected the respective net increase and decrease of CYP3A activity of these regimens. The plasma 4β-hydroxycholesterol level did not indicate a net CYP3A inhibition in the lopinavir/ritonavir arm, possibly because of concomitant enzyme induction. Keywords Antiretroviral . Biomarker . CYP3A . 4β- Hydroxycholesterol . Induction . Inhibition Introduction 4β-Hydroxycholesterol is a metabolite of cholesterol that is present in human plasma [1]. In vitro, 4β-hydroxycholes- Eur J Clin Pharmacol (2008) 64:775–781 DOI 10.1007/s00228-008-0492-8 F. Josephson (*) : L. Bertilsson : Y. Böttiger Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge C1–68, 141 86 Stockholm, Sweden e-mail: filip.josephson@karolinska.se L. Flamholc Department of Infectious Diseases, Malmö University Hospital, Malmö, Sweden M. Gisslén Department of Infectious Diseases, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden V. Ormaasen Department of Infectious Diseases, Ullevål University Hospital, Oslo, Norway A. Sönnerborg Division of Clinical Virology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden A. Sönnerborg Department of Infectious Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden U. Diczfalusy Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden