Skip to main content
SpringerLink
Log in

Probiotics decreased the bioavailability of the bile acid analog, monoketocholic acid, when coadministered with gliclazide, in healthy but not diabetic rats

  • Original Paper
  • Published:
European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

In recent studies we showed that gliclazide has no hypoglycemic effect on type 1 diabetic (T1D) rats while MKC does, and their combination exerted a better hypoglycemic effect than MKC alone. We also showed that the most hypoglycemic effect was noticed when T1D rats were treated with probiotics then gavaged with MKC + gliclazide (blood glucose decreased from 24 ± 3 to 10 ± 2 mmol/l). The aim of this study is to investigate the influence of probiotics on MKC pharmacokinetics when coadministered with gliclazide, in T1D rats. 80 male Wistar rats (weight 350 ± 50 g) were randomly allocated into 8 groups (10 rats/group), 4 of which were injected with alloxan (30 mg/kg) to induce T1D. Group 1 was healthy and group 2 was diabetic. Groups 3 (healthy) and 4 (diabetic) were gavaged with probiotics (75 mg/kg) every 12 h for 3 days and 12 h later all groups received a single oral dose of MKC + gliclazide (4 and 20 mg/kg respectively). The remaining 4 groups were treated in the same way but administered MKC + gliclazide via the i.v. route. Blood samples collected from T1D rats prior to MKC + gliclazide revealed that probiotic treatment alone reduced blood glucose levels twofold. When coadministered with gliclazide, the bioavailability of MKC was reduced in healthy rats treated with probiotics but remained the same in diabetic pretreated rats. The decrease in MKC bioavailability, when administered with gliclazide, caused by probiotic treatment in healthy but not diabetic rats suggests that probiotic treatment induced MKC metabolism or impaired its absorption, only in healthy animals. The different MKC bioavailability in healthy and diabetic rats could be explained by different induction of presystemic elimination of MKC in the gut by probiotic treatment.

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
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Alam MJ, Rahman MA (1971) Changes in the saccharoid fraction in rats with alloxan-induced diabetes or injected with epinephrine. Clin Chem 17(9):915–920

    PubMed  CAS  Google Scholar 

  • Al-Salami H, Kansara H, King J, Morar B, Jayathilaka B, Fawcett PJ et al (2007) Bile acids: a bitter sweet remedy for diabetes. NZ Pharm J 27(10):17–20

    Google Scholar 

  • Al-Salami H, Butt G, Tucker I, Mikov M (2008a) Influence of the semisynthetic bile acid (MKC) on the ileal permeation of gliclazide in healthy and diabetic rats. Pharmacol Reports 2008 60(4):532–541

    CAS  Google Scholar 

  • Al-Salami H, Butt G, Tucker I, Mikov M (2008b) Probiotic treatment reduces blood glucose levels and increases systemic absorption of gliclazide in diabetic rats. Eur J Drug Metab Pharmacokinet 33(2):101–106

    Article  PubMed  CAS  Google Scholar 

  • Al-Salami H, Butt G, Tucker I, Mikov M (2008c) The influence of the symisynthetic bile acids, MKC on gliclazide PKs and glucose levels in healthy and diabetic rats after pre-treatment with probiotics. Med Hypothes and Res 4(2):1–9

    Google Scholar 

  • Al-Salami H, Butt Grant, Tucker Ian, Mikov M (2008d) The influence of probiotics pre-treatment, on the ileal permeation of gliclazide, in healthy and diabetic rats. Archives Drug Inf 1(1):35–41

    Article  CAS  Google Scholar 

  • Al-Salami H, Butt G, Tucker I, Fawcett PJ, Golocorbin-Kon S, Mikov I et al (2009) Gliclazide reduces MKC intestinal transport in healthy but not diabetic rats. Eur J Drug Metab Pharmacokinet 34(1):43–50

    Article  PubMed  CAS  Google Scholar 

  • Bachmann K, Pardoe D, White D (1996) Scaling basic toxicokinetic parameters from rat to man. Environ Health Perspect 104(4):400–407

    Article  PubMed  CAS  Google Scholar 

  • Ballatori N, Christian WV, Lee JY, Dawson PA, Soroka CJ, Boyer JL et al (2005) OSTalpha-OSTbeta: a major basolateral bile acid and steroid transporter in human intestinal, renal, and biliary epithelia. Hepatology 42(6):1270–1279

    Article  PubMed  CAS  Google Scholar 

  • Bengmark S (1998) Ecological control of the gastrointestinal tract. The role of probiotic flora. Gut 42(1):2–7

    Article  PubMed  CAS  Google Scholar 

  • Bezkorovainy A (2001) Probiotics: determinants of survival and growth in the gut. Am J Clin Nutr 73(2 Suppl):399S–405S

    PubMed  CAS  Google Scholar 

  • Bodo A, Bakos E, Szeri F, Varadi A, Sarkadi B (2003) Differential modulation of the human liver conjugate transporters MRP2 and MRP3 by bile acids and organic anions. J Biol Chem 278(26):23529–23537

    Article  PubMed  CAS  Google Scholar 

  • Braaten JT, Faloona GR, Unger RH (1974) The effect of insulin on the alpha-cell response to hyperglycemia in long-standing alloxan diabetes. J Clin Invest 53(4):1017–1021

    Article  PubMed  CAS  Google Scholar 

  • Brinton EA (2008) Novel pathways for glycaemic control in type 2 diabetes: focus on bile acid modulation. Diabetes Obes Metab 10(11):1004–1011

    Article  PubMed  CAS  Google Scholar 

  • Campbell DB, Lavielle R, Nathan C (1991) The mode of action and clinical pharmacology of gliclazide: a review. Diabetes Res Clin Pract 14(Suppl 2):S21–S36

    Article  PubMed  Google Scholar 

  • Cardin S, Walmsley K, Neal DW, Williams PE, Cherrington AD (2002) Involvement of the vagus nerves in the regulation of basal hepatic glucose production in conscious dogs. Am J Physiol Endocrinol Metab 283(5):E958–E964

    PubMed  CAS  Google Scholar 

  • CarvalhoI ENd, CarvalhoII NASd, Ferreira. LM. Experimental model of induction of diabetes mellitus in rats. Acta Cirurgica Brasileira. 2003;18(3):120-67

    Google Scholar 

  • Chen ZS, Guo Y, Belinsky MG, Kotova E, Kruh GD (2005) Transport of bile acids, sulfated steroids, estradiol 17-beta-d-glucuronide, and leukotriene C4 by human multidrug resistance protein 8 (ABCC11). Mol Pharmacol 67(2):545–557

    Article  PubMed  CAS  Google Scholar 

  • Daugherty AL, Mrsny RJ (1999) Transcellular uptake mechanisms of the intestinal epithelial barrier Part one. Pharm Sci Technol Today 4(2):144–151

    Article  PubMed  Google Scholar 

  • DeCarvalhoI E, CarvalhoII N, Ferreira L (2003) Experimental model of induction of diabetes mellitus in rats. Acta Cirurgica Brasileira 18(3):120–167

    Google Scholar 

  • Delrat P, Paraire M, Jochemsen R (2002) Complete bioavailability and lack of food-effect on pharmacokinetics of gliclazide 30 mg modified release in healthy volunteers. Biopharm Drug Dispos 23(4):151–157

    Article  PubMed  CAS  Google Scholar 

  • Devendra D, Liu E, Eisenbarth GS (2004) Type 1 diabetes: recent developments. BMJ 328(7442):750–4

    Google Scholar 

  • Dow J, Lindsay G, Morrison J (1996) Biochemistry molecules, cells and the body. Addison-Wesley Publishing, Boston, pp 418–22

  • Esmaeili MA, Yazdanparast R (2004) Hypoglycaemic effect of teucrium polium: studies with rat pancreatic islets. J Ethnopharmacol 95(1):27–30

    Article  PubMed  Google Scholar 

  • Fallucca F, Sciullo E, Maldonato A (1996) Combined therapy with insulin and sulfonylurea for the treatment of new-onset insulin-dependent diabetes mellitus. Horm Metab Res 28(2):86–88

    Article  PubMed  CAS  Google Scholar 

  • FAO/WHO (2001) Guidelines for the Evaluation of Probiotics in Food 2002

  • Florkowski CM, Richardson MR, Le Guen C, Jennings PE, O’Donnell MJ, Jones AF et al (1988) Effect of gliclazide on thromboxane B2, parameters of haemostasis, fluorescent IgG and lipid peroxides in non-insulin dependent diabetes mellitus. Diabetes Res 9(2):87–90

    PubMed  CAS  Google Scholar 

  • Goldfine AB (2008) Modulating LDL cholesterol and glucose in patients with type 2 diabetes mellitus: targeting the bile acid pathway. Curr Opin Cardiol 23(5):502–511

    Article  PubMed  Google Scholar 

  • Gonzalez J, Hidalgo F, Lopez MA, Esteller A (1983) Influence of bile salts on the endogenous excretion of bile pigments. Rev Esp Fisiol 39(1):69–75

    PubMed  CAS  Google Scholar 

  • Gonzalez-Alvarez I, Fernandez-Teruel C, Casabo-Alos VG, Garrigues TM, Polli JE, Ruiz-Garcia A et al (2007) In situ kinetic modelling of intestinal efflux in rats: functional characterization of segmental differences and correlation with in vitro results. Biopharm Drug Dispos 28(5):229–239

    Article  PubMed  CAS  Google Scholar 

  • Hong SS, Lee SH, Lee YJ, Chung SJ, Lee MH, Shim CK (1998) Accelerated oral absorption of gliclazide in human subjects from a soft gelatin capsule containing a PEG 400 suspension of gliclazide. J Control Release 51(2–3):185–192

    Article  PubMed  CAS  Google Scholar 

  • Houten S, Watanabe M, Auwerx J (2006) Endocrine functions of bile acids. EMBO J 25:1419–1425

    Article  PubMed  CAS  Google Scholar 

  • Huang H, Shan J, Pan XH, Wang HP, Qian LB (2006) Carvedilol protected diabetic rat hearts via reducing oxidative stress. J Zhejiang Univ Sci B 7(9):725–731

    Article  PubMed  CAS  Google Scholar 

  • Jacobs DB, Hayes GR, Lockwood DH (1989) In vitro effects of sulfonylurea on glucose transport and translocation of glucose transporters in adipocytes from streptozocin-induced diabetic rats. Diabetes 38(2):205–211

    Article  PubMed  CAS  Google Scholar 

  • Karimi O, Pena AS (2003) Probiotics: Isolated bacteria strain or mixtures of different strains? Two different approaches in the use of probiotics as therapeutics. Drugs Today (Barc) 39(8):565–597

    Article  CAS  Google Scholar 

  • Khavinson VK (2005) Effect of tetrapeptide on insulin biosynthesis in rats with alloxan-induced diabetes. Bull Exp Biol Med 140(4):452–454

    Article  PubMed  CAS  Google Scholar 

  • Korec R (1980) Treatment of alloxan and streptozotocin diabetes in rats by intrafamiliar homo (allo) transplantation of neonatal pancreases. Endocrinol Exp 14(3):191–198

    PubMed  CAS  Google Scholar 

  • Kramer W, Wess G, Neckermann G, Schubert G, F ink J, Girbig F et al (1994) Intestinal absorption of peptides by coupling to bile acids. J Biol Chem 269(14):10621–10627

    PubMed  CAS  Google Scholar 

  • Krittaphol W, Wescombe PA, Thomson CD, McDowell A, Tagg JR, Fawcett JP (2011a) Metabolism of l-Selenomethionine and Selenite by Probiotic Bacteria: in vitro and in vivo studies. Biol Trace Elem Res

  • Krittaphol W, McDowell A, Thomson CD, Mikov M, Fawcett JP (2011b) Biotransformation of l-selenomethionine and selenite in rat gut contents. Biol Trace Elem Res [Research Support, Non-U.S. Gov’t] 139(2):188–96

    Google Scholar 

  • Kuhajda K, Kevresan S, Mikov M, Sabo A (1997) D. M. 3a, 7a-dihydroxy-12-keto-5β-cholanate as an enhancer of insluin nasal absorption in rats. Arch Toxicol Kinet Xenobiot 5:359–361

    Google Scholar 

  • Levy P (2008) Bile acid sequestrants as a therapeutic option for glucose lowering in type 2 diabetes mellitus. Endocr Pract 14(5):644–647

    PubMed  Google Scholar 

  • Madsen D, Beaver M, Chang L, Bruckner-Kardoss E, Wostmann B (1976) Analysis of bile acids in conventional and germfree rats. J Lipid Res 17(2):107–111

    PubMed  CAS  Google Scholar 

  • Meinders AE, Van Berge Henegouwen GP, Willekens FL, Schwerzel AL, Ruben A, Huybregts AW (1981) Biliary lipid and bile acid composition in insulin-dependent diabetes mellitus. Arguments for increased intestinal bacterial bile acid degradation. Dig Dis Sci 26(5):402–408

    Article  PubMed  CAS  Google Scholar 

  • Merlob P, Levitt O, Stahl B (2002) Oral antihyperglycemic agents during pregnancy and lactation: a review. Paediatr Drugs 4(11):755–760

    PubMed  Google Scholar 

  • Mikov M, Fawcett JP (2006) Chemistry, biosynthesis, analysis, chemical & metabolic transformations and pharmacology. Eur J Drug Metab Pharmacokinet 31(3):133–134

    Article  PubMed  CAS  Google Scholar 

  • Mikov M, Fawcett JP, Kuhajda K, Kevresan S (2006) Pharmacology of bile acids and their derivatives: absorption promoters and therapeutic agents. Eur J Drug Metab Pharmacokinet 31(3):237–251

    Article  PubMed  CAS  Google Scholar 

  • Mikov M, Boni NS, Al-Salami H, Kuhajda K, Kevresan S, Golocorbin-Kon S et al (2007) Bioavailability and hypoglycemic activity of the semisynthetic bile acid salt, sodium 3alpha, 7alpha-dihydroxy-12-oxo-5beta-cholanate, in healthy and diabetic rats. Eur J Drug Metab Pharmacokinet 32(1):7–12

    Article  PubMed  CAS  Google Scholar 

  • Mikov M, Al-Salami H, Fawcett JP (2008) The influence of 3a, 7a-dihydroxy-12-keto-5β-cholanate on gliclazide pharmacokinetics and glucose levels in a rat model of diabetes. Eur J Drug Metab Pharmacokinet 33(3):137–142

    Article  PubMed  CAS  Google Scholar 

  • Miljkovic D, Kuhajda K, (1996) J. H. Selective C-12 oxidation of cholic acid. Chem Res 2(1):106–7

  • Mita S, Suzuki H, Akita H, Hayashi H, Onuki R, Hofmann AF et al (2006) Inhibition of bile acid transport across Na+/taurocholate cotransporting polypeptide (SLC10A1) and bile salt export pump (ABCB 11)-coexpressing LLC-PK1 cells by cholestasis-inducing drugs. Drug Metab Dispos 34(9):1575–1581

    Article  PubMed  CAS  Google Scholar 

  • Moursagaleeva G, Khafizianova RK, Kiyasov AP (1998) The elevating blood glucose levels as result of increasing of A-cell population in alloxan-induced diabetes in rats. Pathophysiology 5(Suppl 1):177

    Google Scholar 

  • Noda Y, Mori A, Packer L (1997) Gliclazide scavenges hydroxyl, superoxide and nitric oxide radicals: an ESR study. Res Commun Mol Pathol Pharmacol 96(2):115–124

    PubMed  CAS  Google Scholar 

  • Palmer KJ, Brogden RN (1993) Gliclazide. An update of its pharmacological properties and therapeutic efficacy in non-insulin-dependent diabetes mellitus. Drugs 46(1):92–125

    Google Scholar 

  • Pigeon RM, Cuesta EP, Gililliand SE (2002) Binding of free bile acids by cells of yogurt starter culture bacteria. J Dairy Sci 85(11):2705–2710

    Article  PubMed  CAS  Google Scholar 

  • Ponz De Leon M, Ferenderes R, Carulli N (1976) Bile composition in patients with high risk of cholelithiasis. Minerva Med 67(53):3483–3490

    PubMed  CAS  Google Scholar 

  • Reasner CA (2008) Reducing cardiovascular complications of type 2 diabetes by targeting multiple risk factors. J Cardiovasc Pharmacol 52(2):136–144

    Article  PubMed  CAS  Google Scholar 

  • Renier G, Desfaits AC, Serri O (2000) Effect of gliclazide on monocyte-endothelium interactions in diabetes. J Diabetes Complicat 14(4):215–223

    Article  PubMed  CAS  Google Scholar 

  • Rieutord A, Stupans I, Shenfield GM, Gross AS (1995) Gliclazide hydroxylation by rat liver microsomes. Xenobiotica 25(12):1345–1354

    Article  PubMed  CAS  Google Scholar 

  • Roberts MS, Magnusson BM, Burczynski FJ, Weiss M (2002) Enterohepatic circulation: physiological, pharmacokinetic and clinical implications. Clin Pharmacokinet 41(10):751–790

    Article  PubMed  CAS  Google Scholar 

  • Rozanova GN, Voevodin DA, Stenina MA, Kushnareva MV (2002) Pathogenetic role of dysbacteriosis in the development of complications of type 1 diabetes mellitus in children. Bull Exp Biol Med 133(2):164–166

    Article  PubMed  CAS  Google Scholar 

  • Rudman D, Kendall FE (1957a) Bile acid content of human serum. II. The binding of cholanic acids by human plasma proteins. J Clin Invest 36(4):538–542

    Article  PubMed  CAS  Google Scholar 

  • Rudman D, Kendall FE (1957b) Bile acid content of human serum. I. Serum bile acids in patients with hepatic disease. J Clin Invest 36(4):530–537

    Article  PubMed  CAS  Google Scholar 

  • Satoh J, Takahashi K, Takizawa Y, Ishihara H, Hirai M, Katagiri H et al (2005) Secondary sulfonylurea failure: comparison of period until insulin treatment between diabetic patients treated with gliclazide and glibenclamide. Diabetes Res Clin Pract 70(3):291–297

    Article  PubMed  CAS  Google Scholar 

  • Setchell KD, Worthington J (1982) A rapid method for the quantitative extraction of bile acids and their conjugates from serum using commercially available reverse-phase octadecylsilane bonded silica cartridges. Clin Chim Acta 125(2):135–144

    Article  PubMed  CAS  Google Scholar 

  • Shaham O, Wei R, Wang TJ, Ricciardi C, Lewis GD, Vasan RS et al (2008) Metabolic profiling of the human response to a glucose challenge reveals distinct axes of insulin sensitivity. Mol Syst Biol 4:214

    Article  PubMed  Google Scholar 

  • Simoni P, Cerre C, Cipolla A, Polimeni C, Pistillo A, Ceschel G et al (1995) Bioavailability study of a new, sinking, enteric-coated ursodeoxycholic acid formulation. Pharmacol Res 31(2):115–119

    Article  PubMed  CAS  Google Scholar 

  • Smith RJ (1990) Effects of the sulfonylureas on muscle glucose homeostasis. Am J Med 89(2A):38S–43S (discussion 51S-3S)

    Article  PubMed  CAS  Google Scholar 

  • Stetinova V, Kvetina J, Pastera J, Polaskova A, Prazakova M (2007) Gliclazide: pharmacokinetic-pharmacodynamic relationships in rats. Biopharm Drug Dispos 28(5):241–248

    Article  PubMed  CAS  Google Scholar 

  • Szkudelski T (2001) The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res 50(6):537–546

    PubMed  CAS  Google Scholar 

  • Uchida K, Makino S, Akiyoshi T (1985) Altered bile acid metabolism in nonobese, spontaneously diabetic (NOD) mice. Diabetes 34(1):79–83

    Article  PubMed  CAS  Google Scholar 

  • Yang L, Zhang H, Mikov M, Tucker IG (2009) Physicochemical and biological characterization of monoketocholic acid, a novel permeability enhancer. Molecular Pharmaceutics [Research Support, Non-U.S. Gov’t] 6(2):448–56

    Google Scholar 

  • Ziegler AG, Schmid S, Huber D, Hummel M, Bonifacio E (2003) Early infant feeding and risk of developing type 1 diabetes-associated autoantibodies. JAMA 290(13):1721–1728

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by a University of Otago Research Grant. Probiotic bacteria were a kind gift of Professor John Tagg, Microbiology Department, University of Otago, Dunedin, New Zealand.

Author information

Authors and Affiliations

  1. School of Pharmacy, University of Otago, Dunedin, New Zealand

    Hani Al-Salami & Ian Tucker

  2. Department of Physiology, University of Otago, Dunedin, New Zealand

    Grant Butt

  3. Department of Pharmacy, Medical Faculty Novi Sad, Novi Sad, Serbia

    Svetlana Golocorbin-Kon

  4. Department of Pharmacology and Toxicology, Medical Faculty Novi Sad, Novi Sad, Serbia

    Momir Mikov

Authors
  1. Hani Al-Salami
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Grant Butt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ian Tucker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Svetlana Golocorbin-Kon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Momir Mikov
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hani Al-Salami.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Al-Salami, H., Butt, G., Tucker, I. et al. Probiotics decreased the bioavailability of the bile acid analog, monoketocholic acid, when coadministered with gliclazide, in healthy but not diabetic rats. Eur J Drug Metab Pharmacokinet 37, 99–108 (2012). https://doi.org/10.1007/s13318-011-0060-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13318-011-0060-y

Keywords

Search

Navigation