Inherited and Acquired Determinants of Hepatic CYP3A Activity in Humans

Johannes Matthaei, Wagner Hugo Bonat, Reinhold Kerb, Mladen Vassilev Tzvetkov, Jakob Strube, Stefanie Brunke, Cordula Sachse-Seeboth, Daniel Sehrt, Ute Hofmann, Jacob von Bornemann Hjelmborg, Matthias Schwab, Jürgen Brockmöller, Johannes Matthaei, Wagner Hugo Bonat, Reinhold Kerb, Mladen Vassilev Tzvetkov, Jakob Strube, Stefanie Brunke, Cordula Sachse-Seeboth, Daniel Sehrt, Ute Hofmann, Jacob von Bornemann Hjelmborg, Matthias Schwab, Jürgen Brockmöller

Abstract

Human CYP3A enzymes (including CYP3A4 and CYP4A5) metabolize about 40% of all drugs and numerous other environmental and endogenous substances. CYP3A activity is highly variable within and between humans. As a consequence, therapy with standard doses often results in too low or too high blood and tissue concentrations resulting in therapeutic failure or dose-related adverse reactions. It is an unanswered question how much of the big interindividual variation in CYP3A activity is caused by genetic or by environmental factors. This question can be answered by the twin study approach. Using midazolam as CYP3A probe drug, we studied 43 monozygotic and 14 dizygotic twins and measured midazolam and its metabolite 1-OH-midazolam. In addition, endogenous biomarkers of CYP3A activity, 4ß-OH-cholesterol and 6ß-OH-cortisol, were analyzed. Additive genetic effects accounted for only 15% of the variation in midazolam AUC, whereas 48% was attributed to common environmental factors. In contrast, 73, 56, and 31% of 1-OH-midazolam, 4ß-OH-cholesterol and 6ß-OH-cortisol variation was due to genetic effects. There was a low phenotypic correlation between the four CYP3A biomarkers. Only between midazolam and its 1-OH-metabolite, and between midazolam and 6ß-OH-cortisol we found significant bivariate genetic correlations. Midazolam AUC differed depending on the CYP3A4∗22 variant (p = 0.001) whereas plasma 4ß-OH-cholesterol was significantly lower in homozygous carriers of CYP3A5∗3 (p = 0.02). Apparently, non-genomic factors played a dominant role in the inter-individual variation of the CYP3A probe drug midazolam. A small intra-individual pharmacokinetic variation after repeated administration of midazolam was rated earlier as indication of high heritability of CYP3A activity, but according to present data that could also largely be due to constant environmental factors and/or heritability of liver blood flow. The higher heritabilities of 4ß-OH-cholesterol and of 1-OH-midazolam may deserve further research on the underlying factors beyond CYP3A genes. Clinical Trial Registration: ClinicalTrials.gov: NCT01845194 and EUDRA-CT: 2008-006223-31.

Keywords: 4ß-OH-cholesterol; 6ß-OH-cortisol; CYP3A; CYP3A4; CYP3A5; heritability; midazolam; twin study.

Copyright © 2020 Matthaei, Bonat, Kerb, Tzvetkov, Strube, Brunke, Sachse-Seeboth, Sehrt, Hofmann, von Bornemann Hjelmborg, Schwab and Brockmöller.

Figures

FIGURE 1
FIGURE 1
Concentration time curves of midazolam (A) and its major metabolite 1-OH-midazolam (B) after intravenous administration of 0.2 mg midazolam. Data for all subjects of one study day are shown. Concentrations of midazolam varied about 10-fold and that of the CYP3A dependent metabolite even higher. Midazolam AUC (C) and 1-OH-midazolam AUC (D) is shown below illustrating the intra-individual variation and the variation between the three study days. The genetic component (Kalow et al., 1998) was determined from this data independently of the twin status, with values of 0.57 (95% CI = 0.54 – 0.60) for the AUC of midazolam and 0.93 (95% CI = 0.93 – 0.94) for the AUC of 1-OH-midazolam.
FIGURE 2
FIGURE 2
Correlation of the biomarkers for CYP3A activity between monozygotic and dizygotic twins. The upper lane shows midazolam AUC. Below is the AUC of 1-OH-midazolam, 4ß-OH-cholesterol in plasma, and 6ß-OH-cortisol in urine over 24 h. Data represents the mean of three measurements performed on separate days.
FIGURE 3
FIGURE 3
Correlations between the four indicators of CYP3A activity: plasma AUC of midazolam and 1-OH-midazolam, plasma concentration of 4ß-OH-cholesterol and the amount of 6ß-OH-cortisol excreted in 24-h urine. Linear regression coefficients are shown in the figure (*p < 0.05, **p < 0.01). As seen, there was a relatively high correlation between midazolam and 6ß-OH-cortisol, whereas the CYP3A generated metabolite 1-OH-midazolam did not correlate at all with the alternative endogenous in vivo biomarkers of CYP3A activity. Only frequent genetic polymorphisms with unequivocal functional relevance were considered, the CYP3A4*22 variant conferring low CYP3A4 activity and the CYP3A5*3 variant conferring loss of CYP3A5 activity.

References

    1. Becquemont L., Glaeser H., Drescher S., Hitzl M., Simon N., Murdter T. E., et al. (2006). Effects of ursodeoxycholic acid on P-glycoprotein and cytochrome P450 3A4-dependent pharmacokinetics in humans. Clin. Pharmacol. Therap. 79 449–460. 10.1016/j.clpt.2006.01.005
    1. Bodin K., Andersson U., Rystedt E., Ellis E., Norlin M., Pikuleva I., et al. (2002). Metabolism of 4 beta -hydroxycholesterol in humans. J. Biol. Chem. 277 31534–31540.
    1. Bodin K., Bretillon L., Aden Y., Bertilsson L., Broome U., Einarsson C., et al. (2001). Antiepileptic drugs increase plasma levels of 4beta-hydroxycholesterol in humans: evidence for involvement of cytochrome p450 3A4. J. Biol. Chem. 276 38685–38689. 10.1074/jbc.m105127200
    1. Bodin K., Lindbom U., Diczfalusy U. (2005). Novel pathways of bile acid metabolism involving CYP3A4. Biochim. Biophys. Acta 1687 84–93. 10.1016/j.bbalip.2004.11.003
    1. Bui K., Zhou D., Sostek M., She F., Al-Huniti N. (2016). Effects of CYP3A modulators on the pharmacokinetics of Naloxegol. J. Clin. Pharmacol. 56 1019–1027. 10.1002/jcph.693
    1. Burke R. S., Somasuntharam I., Rearden P., Brown D., Deshmukh S. V., Dipietro M. A., et al. (2014). siRNA-mediated knockdown of P450 oxidoreductase in rats: a tool to reduce metabolism by CYPs and increase exposure of high clearance compounds. Pharm Res 31 3445–3460. 10.1007/s11095-014-1433-0
    1. Chan S. W., Xiao Y., Hu M., Yin O. Q., Chu T. T., Fok B. S., et al. (2016). Associations of the CYP3A5∗3 and CYP3A4∗1G polymorphisms with the pharmacokinetics of oral midazolam and the urinary 6beta-hydroxycortisol/cortisol ratio as markers of CYP3A activity in healthy male Chinese. J. Clin. Pharm. Ther. 41 552–558. 10.1111/jcpt.12433
    1. Diczfalusy U., Miura J., Roh H. K., Mirghani R. A., Sayi J., Larsson H., et al. (2008). 4Beta-hydroxycholesterol is a new endogenous CYP3A marker: relationship to CYP3A5 genotype, quinine 3-hydroxylation and sex in Koreans, Swedes and Tanzanians. Pharmacogenet. Genom. 18 201–208. 10.1097/fpc.0b013e3282f50ee9
    1. Diczfalusy U., Nylen H., Elander P., Bertilsson L. (2011). 4beta-Hydroxycholesterol, an endogenous marker of CYP3A4/5 activity in humans. Br. J. Clin. Pharmacol. 71 183–189. 10.1111/j.1365-2125.2010.03773.x
    1. Dzeletovic S., Breuer O., Lund E., Diczfalusy U. (1995). Determination of cholesterol oxidation products in human plasma by isotope dilution-mass spectrometry. Analyt. Biochem. 225 73–80. 10.1006/abio.1995.1110
    1. Eap C. B., Buclin T., Cucchia G., Zullino D., Hustert E., Bleiber G., et al. (2004a). Oral administration of a low dose of midazolam (75 microg) as an in vivo probe for CYP3A activity. Eur. J. Clin. Pharmacol. 60 237–246.
    1. Eap C. B., Buclin T., Hustert E., Bleiber G., Golay K. P., Aubert A. C., et al. (2004b). Pharmacokinetics of midazolam in CYP3A4- and CYP3A5-genotyped subjects. Eur. J. Clin. Pharmacol. 60 231–236.
    1. Eeckhoudt S. L., Desager J. P., Robert A. R., Leclercq I., Verbeeck R. K., Horsmans Y. (2001). Midazolam and cortisol metabolism before and after CYP3A induction in humans. Int. J. Clin. Pharmacol. Ther. 39 293–299. 10.5414/cpp39293
    1. Evans W. E., Relling M. V. (1999). Pharmacogenomics: translating functional genomics into rational therapeutics. Science 286 487–491. 10.1126/science.286.5439.487
    1. Foster J. A., Houston J. B., Hallifax D. (2011). Comparison of intrinsic clearances in human liver microsomes and suspended hepatocytes from the same donor livers: clearance-dependent relationship and implications for prediction of in vivo clearance. Xenobiotica 41 124–136. 10.3109/00498254.2010.530700
    1. Fromm M. F., Schwilden H., Bachmakov I., Konig J., Bremer F., Schuttler J. (2007). Impact of the CYP3A5 genotype on midazolam pharmacokinetics and pharmacodynamics during intensive care sedation. Eur. J. Clin. Pharmacol. 63 1129–1133. 10.1007/s00228-007-0365-6
    1. Fuhr U., Jetter A., Kirchheiner J. (2007). Appropriate phenotyping procedures for drug metabolizing enzymes and transporters in humans and their simultaneous use in the “cocktail” approach. Clin. Pharmacol. Ther. 81 270–283. 10.1038/sj.clpt.6100050
    1. Galteau M. M., Shamsa F. (2003). Urinary 6beta-hydroxycortisol: a validated test for evaluating drug induction or drug inhibition mediated through CYP3A in humans and in animals. Eur. J. Clin. Pharmacol. 59 713–733. 10.1007/s00228-003-0690-3
    1. Gashaw I., Kirchheiner J., Goldammer M., Bauer S., Seidemann J., Zoller K., et al. (2003). Cytochrome p450 3A4 messenger ribonucleic acid induction by rifampin in human peripheral blood mononuclear cells: correlation with alprazolam pharmacokinetics. Clin. Pharmacol. Ther. 74 448–457. 10.1016/s0009-9236(03)00237-6
    1. Gorski J. C., Jones D. R., Haehner-Daniels B. D., Hamman M. A., O’mara E. M., Jr. (1998). The contribution of intestinal and hepatic CYP3A to the interaction between midazolam and clarithromycin. Clin. Pharmacol. Ther. 64 133–143. 10.1016/s0009-9236(98)90146-1
    1. Greenblatt D. J., Harmatz J. S. (2015). Ritonavir is the best alternative to ketoconazole as an index inhibitor of cytochrome P450-3A in drug-drug interaction studies. Br. J. Clin. Pharmacol. 80 342–350. 10.1111/bcp.12668
    1. Heizmann P., Eckert M., Ziegler W. H. (1983). Pharmacokinetics and bioavailability of midazolam in man. Br. J. Clin. Pharmacol. 16(Suppl. 1), 43S–49S. 10.1111/j.1365-2125.1983.tb02270.x
    1. Hume R. (1966). Prediction of lean body mass from height and weight. J. Clin. Pathol. 19 389–391. 10.1136/jcp.19.4.389
    1. Kalow W., Endrenyi L., Tang B. (1999). Repeat administration of drugs as a means to assess the genetic component in pharmacological variability. Pharmacology 58 281–284. 10.1159/000028292
    1. Kalow W., Tang B. K., Endrenyi L. (1998). Hypothesis: comparisons of inter- and intra-individual variations can substitute for twin studies in drug research. Pharmacogenetics 8 283–289. 10.1097/00008571-199808000-00001
    1. Kashuba A. D., Bertino J. S., Jr., Rocci M. L., Jr., Kulawy R. W. (1998). Quantification of 3-month intraindividual variability and the influence of sex and menstrual cycle phase on CYP3A activity as measured by phenotyping with intravenous midazolam. Clin. Pharmacol. Ther. 64 269–277. 10.1016/s0009-9236(98)90175-8
    1. Kasichayanula S., Boulton D. W., Luo W. L., Rodrigues A. D., Yang Z., Goodenough A., et al. (2014). Validation of 4beta-hydroxycholesterol and evaluation of other endogenous biomarkers for the assessment of CYP3A activity in healthy subjects. Br. J. Clin. Pharmacol. 78 1122–1134. 10.1111/bcp.12425
    1. Kim H., Yoon Y. J., Shon J. H., Cha I. J., Shin J. G., Liu K. H. (2006). Inhibitory effects of fruit juices on CYP3A activity. Drug Metab. Dispos. 34 521–523. 10.1124/dmd.105.007930
    1. Kirby B., Kharasch E. D., Thummel K. T., Narang V. S., Hoffer C. J., Unadkat J. D. (2006). Simultaneous measurement of in vivo P-glycoprotein and cytochrome P450 3A activities. J. Clin. Pharmacol. 46 1313–1319. 10.1177/0091270006292625
    1. Klein K., Zanger U. M. (2013). Pharmacogenomics of cytochrome P450 3A4: recent progress toward the “missing heritability”. Problem. Front. Genet. 4:12. 10.3389/fgene.2013.00012
    1. Koch I., Weil R., Wolbold R., Brockmoller J., Hustert E., Burk O., et al. (2002). Interindividual variability and tissue-specificity in the expression of cytochrome P450 3A mRNA. Drug Metab. Dispos. 30 1108–1114. 10.1124/dmd.30.10.1108
    1. Kronbach T., Mathys D., Umeno M., Gonzalez F. J., Meyer U. A. (1989). Oxidation of midazolam and triazolam by human liver cytochrome P450IIIA4. Mol. Pharmacol. 36 89–96.
    1. Link B., Haschke M., Grignaschi N., Bodmer M., Aschmann Y. Z., Wenk M., et al. (2008). Pharmacokinetics of intravenous and oral midazolam in plasma and saliva in humans: usefulness of saliva as matrix for CYP3A phenotyping. Br. J. Clin. Pharmacol. 66 473–484. 10.1111/j.1365-2125.2008.03201.x
    1. Lutjohann D., Bjorkhem I., Beil U. F., Von Bergmann K. (1995). Sterol absorption and sterol balance in phytosterolemia evaluated by deuterium-labeled sterols: effect of sitostanol treatment. J. Lipid Res. 36 1763–1773.
    1. Matthaei J., Brockmoller J., Tzvetkov M. V., Sehrt D., Sachse-Seeboth C., Hjelmborg J. B., et al. (2015). Heritability of metoprolol and torsemide pharmacokinetics. Clin. Pharmacol. Ther. 98 611–621. 10.1002/cpt.258
    1. Nies A. S., Shand D. G., Wilkinson G. R. (1976). Altered hepatic blood flow and drug disposition. Clin. Pharmacokinet. 1 135–155. 10.2165/00003088-197601020-00005
    1. Ohno M., Yamaguchi I., Ito T., Saiki K., Yamamoto I., Azuma J. (2000). Circadian variation of the urinary 6beta-hydroxycortisol to cortisol ratio that would reflect hepatic CYP3A activity. Eur. J. Clin. Pharmacol. 55 861–865. 10.1007/s002280050708
    1. Ozdemir V., Kalow W., Tang B. K., Paterson A. D., Walker S. E., Endrenyi L., et al. (2000). Evaluation of the genetic component of variability in CYP3A4 activity: a repeated drug administration method. Pharmacogenetics 10 373–388.
    1. Patki K. C., Von Moltke L. L., Greenblatt D. J. (2003). In vitro metabolism of midazolam, triazolam, nifedipine, and testosterone by human liver microsomes and recombinant cytochromes p450: role of cyp3a4 and cyp3a5. Drug Metab. Dispos. 31 938–944. 10.1124/dmd.31.7.938
    1. Rahmioglu N., Heaton J., Clement G., Gill R., Surdulescu G., Zlobecka K., et al. (2011). Genetic epidemiology of induced CYP3A4 activity. Pharmacogenet. Genom. 21 642–651. 10.1097/fpc.0b013e3283498ecf
    1. Roots I., Saalfrank K., Hildebrandt A. G. (1975). Comparison of methods to study enzyme induction in man. Adv. Exp. Med. Biol. 58 485–502. 10.1007/978-1-4615-9026-2_33
    1. Seo K. A., Bae S. K., Choi Y. K., Choi C. S., Liu K. H., Shin J. G. (2010). Metabolism of 1’- and 4-hydroxymidazolam by glucuronide conjugation is largely mediated by UDP-glucuronosyltransferases 1A4, 2B4, and 2B7. Drug Metab. Dispos. 38 2007–2013. 10.1124/dmd.110.035295
    1. Shin K. H., Ahn L. Y., Choi M. H., Moon J. Y., Lee J., Jang I. J., et al. (2016). Urinary 6beta-Hydroxycortisol/cortisol ratio most highly correlates with midazolam clearance under hepatic CYP3A inhibition and induction in females: a pharmacometabolomics approach. AAPS J. 18 1254–1261. 10.1208/s12248-016-9941-y
    1. Stingl J. C., Bartels H., Viviani R., Lehmann M. L., Brockmoller J. (2014). Relevance of UDP-glucuronosyltransferase polymorphisms for drug dosing: a quantitative systematic review. Pharmacol. Ther. 141 92–116. 10.1016/j.pharmthera.2013.09.002
    1. Tateishi T., Watanabe M., Nakura H., Asoh M., Shirai H., Mizorogi Y., et al. (2001). CYP3A activity in European American and Japanese men using midazolam as an in vivo probe. Clin. Pharmacol. Ther. 69 333–339. 10.1067/mcp.2001.115447
    1. Thiel C., Schneckener S., Krauss M., Ghallab A., Hofmann U., Kanacher T., et al. (2015). A systematic evaluation of the use of physiologically based pharmacokinetic modeling for cross-species extrapolation. J. Pharm. Sci. 104 191–206. 10.1002/jps.24214
    1. Thummel K. E., Shen D. D., Podoll T. D., Kunze K. L., Trager W. F., Hartwell P. S., et al. (1994). Use of midazolam as a human cytochrome P450 3A probe: I. In vitro-in vivo correlations in liver transplant patients. J. Pharmacol. Exp. Ther. 271 549–556.
    1. Tomalik-Scharte D., Lutjohann D., Doroshyenko O., Frank D., Jetter A., Fuhr U. (2009). Plasma 4beta-hydroxycholesterol: an endogenous CYP3A metric? Clin. Pharmacol. Ther. 86 147–153. 10.1038/clpt.2009.72
    1. Tomalik-Scharte D., Suleiman A. A., Frechen S., Kraus D., Kerkweg U., Rokitta D., et al. (2014). Population pharmacokinetic analysis of circadian rhythms in hepatic CYP3A activity using midazolam. J. Clin. Pharmacol. 54 1162–1169. 10.1002/jcph.318
    1. Winkler G., Doring A. (1998). Validation of a short qualitative food frequency list used in several German large scale surveys. Z. Ernahrungswiss 37 234–241. 10.1007/pl00007377

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi