Skip to main content

Advertisement

SpringerLink
Log in

Effects of ursodeoxycholic acid on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam in healthy volunteers

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

Animal and in vitro studies suggest that ursodeoxycholic acid (UDCA) can induce cytochrome P450 3A (CYP3A) expression and enhance its activities. On the other hand, Becquemont et al. demonstrated that UDCA had no influence on intestinal CYP3A activities. The aim of this study was to investigate the effects of UDCA on the intestinal and hepatic CYP3A activities by administration of midazolam (MDZ), as a specific probe for CYP3A activity, in humans. This was a randomized, open-label, crossover study with two phases in 14 healthy volunteers. The volunteers received UDCA (300 mg/day) or placebo orally for 9 days. The pharmacokinetics and pharmacodynamics of intravenous MDZ (5 μg/kg) and oral MDZ (15 μg/kg) were assessed on days 8 and 9, respectively. The pharmacodynamics of MDZ was estimated by measuring peak saccadic velocity, postural away length, critical fusion flicker frequency, and visual analogue scale. UDCA did not affect the pharmacokinetic and pharmacodynamic parameters of intravenous and oral MDZ administrations. Our study suggests that the clinical dosage of UDCA could not affect both hepatic and intestinal CYP3A activities and that the drug interaction between UDCA and substrates for CYP3A is unlikely in humans.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Amlot R, Walker R, Driver J, Spence C (2003) Multimodal visual−soma-to-sensory integration in saccade generation. Neuropsychologia 41:1–15

    Article  PubMed  Google Scholar 

  • Becquemont L, Glaeser, H, Drescher, S, Hitzl M, Simon N, Murdter TE, Heinkele G, Hofmann U, Schaefer C, Burk O, Verstuyft C, Eichelbaum M, Fromm MF (2006) Effects of ursodeoxycholic acid on p-glycoprotein and cytochrome P450 3A4-dependent pharmacokinetics in humans. Clin Pharmacol Ther 79:449–460

    Article  PubMed  CAS  Google Scholar 

  • Bertz RJ, Granneman GR (1997) Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions. Clin Pharmacokinet 32:210–258

    Article  PubMed  CAS  Google Scholar 

  • Bock HH, Lammert F (2002) Nuclear xeno-sensors as a receptors for cholestatic bile acid: the second line of defense. Hepatology 35:232–234

    Article  PubMed  Google Scholar 

  • Bodin K, Bretillon L, Aden Y, Bertilsson L, Broomé U, Einarsson C, Diczfalusy U (2001) Antiepileptic drugs increase plasma levels of 4 beta-hydroxycholesterolin humans: evidence for involvement of cytochrome P450 3A4. J Biol Chem 276:38685–38689

    Article  PubMed  CAS  Google Scholar 

  • Bodin K, Lindbom U, Diczfalusy U (2005) Novel pathways of biocile acid metabolism involving CYP3A4. Biochim Biophys Acta 1687:84–93

    PubMed  CAS  Google Scholar 

  • Bond A, Lader M (1974) The use of analogue scale in rating subjective feelings. Br J Med Psychol 47:211–218

    Google Scholar 

  • Burk O, Wojnowski L (2004) Cytochrome P450 3A and their regulation. Naunyn-Schmiedeberg’s Arch Pharmacol 369:105–124

    Article  CAS  Google Scholar 

  • Dey A, Yadav S, Dhawan A, Seth PK, Parmar D (2006) Evidence for cytochrome P450 3A expression and catalytic activity in rat blood lymphocytes. Life Sci 79:1729–1735

    Article  PubMed  CAS  Google Scholar 

  • Domanski TL, Finta C, Halpert JR, Zaphiropoulos PG (2001) cDNA cloning and initial characterization of CYP3A43, a novel human cytochrome P450. Mol Pharmacol 59:386–392

    PubMed  CAS  Google Scholar 

  • Dostalek M, Pistovcakova J, Jurica J, Tomandl J, Linhart I, Sulcová A, Hadasova E (2005) Effect of St John’s wort (Hypericum perforatum) on cytochrome P-450 activity in perfused rat liver. Life Sci 78:239–244

    Article  PubMed  CAS  Google Scholar 

  • Emoto C, Murase S, Sawada Y, Jones BC, Iwasaki K (2003) In vitro inhibitory effect of 1-aminobenzotriazole on drug oxidations catalyzed by human cytochrome P450 enzymes: a comparison with SKF-525A. Drug Metab Pharmacokinet 18:287–295

    Article  PubMed  CAS  Google Scholar 

  • Emoto C, Murase S, Sawada Y, Iwasaki K (2005) In vitro inhibitory effect of 1-aminobenzotriazole on drug oxidations in human liver microsomes: a comparison with SKF-525A. Drug Metab Pharmacokinet 20:351–357

    Article  PubMed  CAS  Google Scholar 

  • Floyd MD, Gervasini G, Masica AL, Mayo G, George ALJ, Bhat K, Kim RB, Wilkinson G (2003) Genotype-phenotype associations for common CYP3A4 and CYP3A5 variants in the basal and induced metabolism of midazolam in European- and African-American men and women. Pharmacogenetics 13:595–606

    Article  PubMed  CAS  Google Scholar 

  • Guengerich FP (1999) Cytochrome P-450 3A4: regulation and role in drug metabolism. Annu Rev Pharmacol Toxicol 39:1–17

    Article  PubMed  CAS  Google Scholar 

  • Kosuge K, Yang J, Watanabe H, Kimura M, Nishimoto M, Ishizaki T, Ohashi K (2001) Effects fo CYP3A4 inhibition by diltiazem on pharmacokinetics and dynamics of diazepam in relation to CYP2C19 genotype status. Drug Metab Dispos 29:1284–1289

    PubMed  CAS  Google Scholar 

  • Krecic-Shepard ME, Barnas CR, Slimko J, Gorski JC, Wainer IW, Schwartz JB (1999) In vivo comparison of putative probes of CYP3A4/5 activity: erythromycin, dextromethorphan, and verapamil. Clin Pharmacol Ther 66:40–50

    Article  PubMed  CAS  Google Scholar 

  • Kupferschmidt HH, Ha HR, Ziegler WH, Meier PJ, Krähenbühl S (1995) Interaction between grapefruit juice and midazolam in humans. Clin Pharmacol Ther 58:20–28

    Article  PubMed  CAS  Google Scholar 

  • Lown KS, Kolars JC, Thummel KE, Barnett JL, Kunze KL, Wrighton SA, Watkins PB (1994) Interpatient heterogeneity in expression of CYP3A4 and CYP3A5 in small bowel: lack of prediction by the erythromycin breath test. Drug Metab Dispos 22:947–955

    PubMed  CAS  Google Scholar 

  • Macias RI, Jimenez S, Serrano MA, Monte MJ, Marin JJ (2006) Effect of maternal cholestasis and treatment with ursodeoxycholic acid on the expression of genes involved in the secretion of biliary lipids by the neonatal rat liver. Life Sci 79:1014–1019

    Article  PubMed  CAS  Google Scholar 

  • Mc Donnell CG, Harte S, O’Driscoll J, O’Louahlin C, Van Pelt FD, Shorten GD (2003) The effects of concurrent atorvastatin therapy on the pharmacokinetics of intravenous midazolam. Anaesthesia 58:899–904

    Article  PubMed  CAS  Google Scholar 

  • Olkkola KT, Aranko K, Luurila H, Hiller A, Saarnivaara L, Himberg JJ, Neuvonen P (1993) A potentially hazardous interaction between erythromycin and midazolam. Clin Pharmacol Ther 53:298–305

    Article  PubMed  CAS  Google Scholar 

  • Paine MF, Shen DD, Kunze KL, Perkins JD, Marsh CL, McVicar JP, Barr DM, Gillies BS, Thummel KE (1996) First-pass metabolism of midazolam by the human intestine. Clin Pharmacol Ther 60:14–24

    Article  PubMed  CAS  Google Scholar 

  • Paolini M, Pozzetti L, Montagnani M, Potenza G, Sabatini L, Antelli A, Cantelli-Forti G, Roda A (2002) Ursodeoxycholic acid (UDCA) prevents DCA effects on male mouse liver via up-regulation of CXP and preservation of BSEP activities. Hepatology 36:305–314

    Article  PubMed  CAS  Google Scholar 

  • Paumgartner G, Beuers U (2002) Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Hepatology 36:525–31

    Article  PubMed  CAS  Google Scholar 

  • Rebbeck TR, Jaffe JM, Walker AH, Wein AJ, Malkowicz SB (1998) Modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4. J Natl Cancer Inst 90:1225–1229

    Article  PubMed  CAS  Google Scholar 

  • Schuetz EG, Schuetz JD, Strom SC, Thompson MT, Fisher RA, Molowa DT, Li D, Guzelian PS (1993) Regulation of human liver cytochromes P-450 in family 3A in primary and continuous culture of human hepatocyte. Hepatology 18:1254–1262

    PubMed  CAS  Google Scholar 

  • Schuetz EG, Strom S, Yasuda K, Lecureur V, Assem M, Brimer C, Lamba J, Kim RB, Ramachandran V, Komoroski BJ, Venkataramanan R, Cai H, Sinal CJ, Gonzalez FJ, Schuetz JD (2001) Disrepted bile acid homeostasis reveals an unexpected interaction among nuclear hormone receptors, transporters, and cytochrome P450. J Biol Chem 276:39411–39418

    Article  PubMed  CAS  Google Scholar 

  • Shimada T, Gillam EMJ, Sandhu P, Guo Z, Tukey RH, Guengerich FP (1994) Activation of procarcinogens by human cytochrome P450 enzymes expressed in Escherichia coli. Simplified bacterial systems for genotoxicity assays. Carcinogenesis 15:2523–2529

    Article  PubMed  CAS  Google Scholar 

  • Strelevitz TJ, Foti RS, Fisher MB (2006) In vivo use of the P450 inactivator 1-aminobenzotriazole in the rat: varied dosing route to elucidate gut and liver contributions to first-pass and systemic clearance. J Pharm Sci 95:1334–1341

    Article  PubMed  CAS  Google Scholar 

  • Theofilopoulos N, Szabadi E, Bradshaw CM (1984) Comparison of the effects of ranitidine and thioridazine on psychomotor functions in healthy volunteers. Br J Clin Pharmacol 18:135–144

    PubMed  CAS  Google Scholar 

  • Thomas AW, White KP, Drost DJ, Cook CM, Prato FS (2001) A comparison of rheumatoid arthritis and fibromyalagia patients and healthy controls exposed to a pulsed (200 micro T) magnetic field: effects on normal standing balance. Neurosci Lett 309:17–20

    Article  PubMed  CAS  Google Scholar 

  • Thummel KE, O’Shea D, Paine MF, Shen DD, Kunze KL, Perkins JD, Wilkinson GR (1996) Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism. Clin Pharmacol Ther 59:491–502

    Article  PubMed  CAS  Google Scholar 

  • Thummel KE, Kunze KL, Shen DD (1997) Enzyme-catalyzed processes of first-pass hepatic and intestinal drug extraction. Adv Drug Del Rev 27:99–127

    Article  CAS  Google Scholar 

  • Tsunoda SM, Velez RL, von-Moltke L, Gre-Lenbl DJ (1999) Differentiation of intestinal and hepatic cytochrome P450 3A activity with use of midazolam as an in vivo probe: effect of ketoconazole. Clin Pharmacol Ther 66:461–471

    Article  PubMed  CAS  Google Scholar 

  • Van SA, Kroon J, Schoemaker H, Pieterss P, Breimer D, Cohen A (1991) A comparison of the sensitivities of adaptive tracking, eye movement analysis and visual analogue lines to the effects of incremental doses of temazepam in healthy volunteers. Clin Pharmacol Ther 50:172–180

    Article  Google Scholar 

  • Wandel C, Böcker R, Böhrer H, Browne A, Rüghrimer E, Martin E (1994) Midazolam is metabolized by at least three different cytochrome P450 enzymes. Br J Anaesthe 73:658–661

    Article  CAS  Google Scholar 

  • Watkins PB (1994) Noninvasive tests of CYP3A enzymes. Pharmacogenetics 4:171–184

    Article  PubMed  CAS  Google Scholar 

  • Westlind A, Malmebo S, Johansson I, Otter C, Andersson TB, Ingelman-Sundberg M, Oscarson M (2001) Cloning and tissue distribution of a novel human cytochrome p450 of the CYP3A subfamily, CYP3A43. Biochem Biophys Res Commun 281:1349–1355

    Article  PubMed  CAS  Google Scholar 

  • Zolner G, Fickert P, Silbert D, Fuchsbichler A, Marschall HU, Zatloukal K, Denk H, Trauner M (2003) Adaptive changes in hepatobiliary transporter expression in primary biliary cirrhosis. J Hepatol 38:717–727

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, 431-3129, Japan

    Dongmei Yan, Yingbao Yang, Jinghui Luo, Kazuhiko Takeuchi, Naoki Inui & Hiroshi Watanabe

  2. Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, 422-8526, Japan

    Sinya Uchida, Shingen Misaka & Shizuo Yamada

  3. Department of Clinical Pharmacology and Therapeutics, Oita University Faculty of Medicine, Oita, 879-5593, Japan

    Kyoichi Ohashi

Authors
  1. Dongmei Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yingbao Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sinya Uchida
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shingen Misaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jinghui Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kazuhiko Takeuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Naoki Inui
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shizuo Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kyoichi Ohashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hiroshi Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hiroshi Watanabe.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yan, D., Yang, Y., Uchida, S. et al. Effects of ursodeoxycholic acid on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam in healthy volunteers. Naunyn-Schmied Arch Pharmacol 377, 629–636 (2008). https://doi.org/10.1007/s00210-007-0217-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-007-0217-z

Keywords

Search

Navigation