Influence of CYP1A1 induction by cigarette smoke on pharmacokinetics of erlotinib: a computer-based evaluation of smoke-induced CYP1A1 activity in different tissues
M. Meyer (1), S. Willmann (1), C. Becker (2), R. Burghaus (2), W. Mueck (2), J. Lippert (1)
(1) Systems Biology and Computational Solutions, Bayer Technology Services GmbH, Leverkusen, Germany; (2) Clinical Pharmacology, Bayer Schering Pharma AG, Wuppertal
Objectives: Human cytochrome P-450 1A1 (CYP1A1) is located primarily in extrahepatic tissues and is known to be inducible by polycyclic aromatic hydrocarbons (PAHs) present in cigarette smoke and chargrilled meat [1-3]. Higher tissue levels of CYP1A1 can lead to a significant reduction in drug exposure in smokers or individuals with high consumption of barbecued meat and thus to a decrease in therapeutic efficacy. In order to evaluate the degree of CYP1A1 induction by tobacco smoke in different tissues, pharmacokinetics of erlotinib, a known substrate of CYP1A1, was analyzed using physiologically-based pharmacokinetic (PBPK) modeling.
Methods: A PBPK model for single dose intravenous (iv) and per oral (po) administration of erlotinib was developed integrating reported relative baseline expression levels for the relevant metabolizing enzymes CYP3A4 and CYP1A1 in liver, lung, and intestine [4, 5]. The model was implemented in the software tools PK-Sim® and MoBi® [6, 7] and adjusted to experimental plasma concentrations  taking into account study data to CYP3A4 inhibition with ketoconazole for estimation of residual CYP1A1 activity  and study data of smokers vs. non-smokers for evaluation of CYP1A1 induction .
Results: Two scenarios were evaluated. The first scenario assumed identical CYP1A1 induction in lung, liver, and intestine, leading to a predicted relative increase in enzymatic activity in all three tissues of 5.5 +/- 0.3 %. The second scenario allowed for local differences in CYP1A1 induction representing the expectation that CYP1A1 induction should be highest in lung since it is the tissue exposed to the highest concentrations of PAHs. In line with this expectation model scenario 2 predicted a relative increase of CYP1A1 activity in smokers of 12 +/- 6 % in lung, 5.4 +/- 0.3 % in liver, and 2.6 +/- 1.2 % in intestine, respectively. The model-based analysis of erlotinib pharmacokinetics in smokers and non-smokers predicted CYP1A1 induction levels in different tissues which are in accordance with experimental expression levels reported in literature [11-13].
Conclusions: PBPK modeling provides a valuable means of predicting drug pharmacokinetics in response to environmental chemicals such as PAHs in cigarette smoke or other compounds known to modify protein expression levels using information to relative changes in enzymatic activities.
 Anttila, S., P. Tuominen, A. Hirvonen, M. Nurminen, A. Karjalainen, O. Hankinson, and E. Elovaara. 2001. CYP1A1 levels in lung tissue of tobacco smokers and polymorphisms of CYP1A1 and aromatic hydrocarbon receptor. Pharmacogenetics 11: 501-509.
 Fontana, R. J., K. S. Lown, M. F. Paine, L. Fortlage, R. M. Santella, J. S. Felton, M. G. Knize, A. Greenberg, and P. B. Watkins. 1999. Effects of a chargrilled meat diet on expression of CYP3A, CYP1A, and P-glycoprotein levels in healthy volunteers. Gastroenterology 117: 89-98.
 Whitlock, J. P., Jr. 1999. Induction of cytochrome P4501A1. Annu Rev Pharmacol Toxicol 39: 103-125.
 Nishimura, M., H. Yaguti, H. Yoshitsugu, S. Naito, and T. Satoh. 2003. Tissue distribution of mRNA expression of human cytochrome P450 isoforms assessed by high-sensitivity real-time reverse transcription PCR. Yakugaku Zasshi 123: 369-375.
 Berggren, S., C. Gall, N. Wollnitz, M. Ekelund, U. Karlbom, J. Hoogstraate, D. Schrenk, and H. Lennernas. 2007. Gene and protein expression of P-glycoprotein, MRP1, MRP2, and CYP3A4 in the small and large human intestine. Mol Pharm 4: 252-257.
 Bayer Technology Services GmbH - MoBi®: The systems biology software tool for multiscale physiological modeling and simulation.: http://www.systems-biology.com/products/mobi.html.
 Willmann, S., J. Lippert, M. Sevestre, J. Solodenko, F. Fois, and W. Schmitt. 2003. PK-Sim©: a physiologically based pharmacokinetic 'whole-body' model. Biosilico 1: 121-124.
 Frohna, P., J. Lu, S. Eppler, M. Hamilton, J. Wolf, A. Rakhit, J. Ling, S. R. Kenkare-Mitra, and B. L. Lum. 2006. Evaluation of the absolute oral bioavailability and bioequivalence of erlotinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in a randomized, crossover study in healthy subjects. J Clin Pharmacol 46: 282-290.
 Rakhit, A., M. P. Pantze, S. Fettner, H. M. Jones, J. E. Charoin, M. Riek, B. L. Lum, and M. Hamilton. 2008. The effects of CYP3A4 inhibition on erlotinib pharmacokinetics: computer-based simulation (SimCYP) predicts in vivo metabolic inhibition. Eur J Clin Pharmacol 64: 31-41.
 Hamilton, M., J. L. Wolf, J. Rusk, S. E. Beard, G. M. Clark, K. Witt, and P. J. Cagnoni. 2006. Effects of smoking on the pharmacokinetics of erlotinib. Clin Cancer Res 12: 2166-2171.
 Chang, T. K., J. Chen, V. Pillay, J. Y. Ho, and S. M. Bandiera. 2003. Real-time polymerase chain reaction analysis of CYP1B1 gene expression in human liver. Toxicol Sci 71: 11-19.
 Smith, G. B., P. A. Harper, J. M. Wong, M. S. Lam, K. R. Reid, D. Petsikas, and T. E. Massey. 2001. Human lung microsomal cytochrome P4501A1 (CYP1A1) activities: impact of smoking status and CYP1A1, aryl hydrocarbon receptor, and glutathione S-transferase M1 genetic polymorphisms. Cancer Epidemiol Biomarkers Prev 10: 839-853.
 Buchthal, J., K. E. Grund, A. Buchmann, D. Schrenk, P. Beaune, and K. W. Bock. 1995. Induction of cytochrome P4501A by smoking or omeprazole in comparison with UDP-glucuronosyltransferase in biopsies of human duodenal mucosa. Eur J Clin Pharmacol 47: 431-435.