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Anti-tuberculosis drug concentrations in tuberculosis patients with and without diabetes mellitus

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The aim of the study was to compare plasma concentrations of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA) between tuberculosis (TB) patients with and without diabetes mellitus (DM).

Methods

Two-hour post-dosing concentrations of RMP, INH and PZA were determined in adult TB patients that were studied with (n = 452) and without DM (n = 1460), treated with a thrice-weekly regimen in India. Drug concentrations were estimated by HPLC.

Results

The median (IQR) INH [6.6 (3.9–10.0) and 7.8 (4.6–11.3)] and PZA [31.0 (22.3–38.0) and 34.1 (24.6–42.7)] microgram per milliliter concentrations were significantly lower in diabetic than non-diabetic TB patients (p < 0.001 for both drugs). Blood glucose was negatively correlated with plasma INH (r = −0.09, p < 0.001) and PZA (r = −0.092, p < 0.001). Multiple linear regression analysis showed RMP, INH and PZA concentrations were influenced by age and drug doses, INH and PZA by DM, RMP by alcohol use and PZA by gender and category of ATT. DM reduced INH and PZA concentrations by 0.8 and 3.0 μg/ml, respectively.

Conclusions

TB patients with DM had lower INH and PZA concentrations. Negative correlation between blood glucose and drug concentrations suggests delayed absorption/faster elimination of INH and PZA in the presence of elevated glucose.

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References

  1. Hu FB, Manson JE, Stampfer MJ, Colditz G, Liu S, Solomon CG, Willett WC (2001) Diet, lifestyle, and the risk of type 2 diabetes mellitus in women. New Engl J Med 345:790–797

    Article  CAS  PubMed  Google Scholar 

  2. Van Dam RM, Rimm EB, Willett WC, Stampfer MJ, Hu FB (2002) Dietary patterns and risk for type 2 diabetes mellitus in US men. Ann Intern Med 136:201–209

    Article  PubMed  Google Scholar 

  3. Popkin BM (2008) Will China’s nutrition transition overwhelm in health care system and slow economic growth? Health Aff (Milwood) 27:1064–1076

    Article  Google Scholar 

  4. Mozaffarian D, Kamineni A, Carnethon M, Djousse L, Mukamal KJ, Siscovick D (2009) Lifestyle risk factors and new-onset diabetes mellitus in older adults: the cardiovascular health study. Arch Intern Med 169:798–807

    Article  PubMed  PubMed Central  Google Scholar 

  5. Dooley KE, Chaisson RE (2009) Tuberculosis and diabetes mellitus: convergence of two epidemics. Lancet Infect Dis 9:737–746

    Article  PubMed  PubMed Central  Google Scholar 

  6. Bashar M, Alcabes P, Rom WN, Condos R (2001) Increased incidence of multidrug-resistant tuberculosis in diabetic patients on the Bellevue Chest Service, 1987 to 1997. Chest 120:1514–1519

    Article  CAS  PubMed  Google Scholar 

  7. Fishet-Hosch SP, Whitney E, McCormick JB, Crespo G, Smith B, Rahbar MH, Restrepo BI (2008) Type 2 diabetes and multidrug-resistant tuberculosis. Scand J Infect Dis 40:888–893

    Article  Google Scholar 

  8. Nijland HMJ, Ruslami R, Stalenhost JE, Alisjahbana B, Nelwan RH, van der Ven AJ, Danusantoso H, Aarnoutse RE, van Crevel R (2006) Exposure to rifampicin is strongly reduced in patients with tuberculosis and type 2 diabetes. Clin Infect Dis 43:848–854

    Article  CAS  PubMed  Google Scholar 

  9. Babalik A, Ulus IH, Bakirci N, Kuyuca T, Arpag H, Dagyildizi L, Capaner E (2013) Plasma concentrations of isoniazid and rifampin are decreased in adult pulmonary tuberculosis patients with diabetes mellitus. Antimicrob Agents Chemother:5740–5742

  10. Revised National TB Control Programme, Annual status report (2011) Central TB Division, Government of India. TB India. 98–101

  11. Abdullah A, Peloquin CA (2014) Therapeutic drug monitoring in the treatment of tuberculosis: an update. Drugs 74:839–854

    Article  Google Scholar 

  12. Hemanth Kumar AK, Immanuel C, Ramachandran G, Chelvi KS, Lalitha V, Prema G (2004) A validated high performance liquid chromatography method for the determination of rifampicin and desacetyl rifampicin in plasma and urine. Indian J Pharmacol 36:231–233

    Google Scholar 

  13. Hemanth Kumar AK, Sudha V, Ramachandran G (2012) Simple and rapid liquid chromatography method for simultaneous determination of isoniazid and pyrazinamide in plasma. SAARC J TB Lung diseases & HIV/AIDS 9:13–18

    Google Scholar 

  14. Hemanth Kumar AK, Kannan T, Chandrasekaran V, Sudha V, Vijayakumar A, Ramesh K, Lavanya J, Swaminathan S, Ramachandran G (2016) Pharmacokinetics of thrice weekly rifampicin, isoniazid and pyrazinamide in adult tuberculosis patients in India. Int J Tuberc Lung Dis 20(9):1236–1241

  15. Singla R, Khan N, Al-Sharif N, Al-Sayegh MO, Shaikh MA, Osman MM (2006) Influence of diabetes on manifestations and treatment outcome of pulmonary TB patients. Int J Tuberc Lung Dis 10:74–79

    CAS  PubMed  Google Scholar 

  16. Wang CS, Yang HC, Chen HC, Chuang SH, Chong IW, Hwang JJ, Huang MS (2009) Impact of type 2 diabetes on manifestations and treatment outcome of pulmonary tuberculosis. Epid Infect 137:203–210

    Article  CAS  Google Scholar 

  17. Chang JT, Dou HY, Yen CL, Wu YH, Huang RM, Lin HJ, Su IJ, Shieh CC (2011) Effect of type 2 diabetes mellitus on the clinical severity and treatment outcome in patients with pulmonary tuberculosis: a potential role in the emergence of multi-drug resistance. J Formos Med Assoc 110:372–381

    Article  PubMed  Google Scholar 

  18. Ruslami R, Nijland HMJ, Adhiarta IGN, Kariadi HKS, Alisjahbana B, Aarnoutse RE, van Crevel R (2010) Pharmacokinetics of antituberculosis drugs in pulmonary tuberculosis patients with type 2 diabetes. Antimicrob Agents Chemother 54:1068–1074

    Article  CAS  PubMed  Google Scholar 

  19. Requena-Mendez A, Davies G, Ardrey A, Jave O, Lopez-Romero SL, Ward SA, Moore DA (2012) Pharmacokinetics of rifampicin in Peruvian tuberculosis patients with and without comorbid diabetes or HIV. Antimicrob Agents Chemother 6:2357–2363

    Article  Google Scholar 

  20. Matuski Y, Katakuse Y, Matsuura H, Kiwada H, Goromaru T (1991) Effects of glucose and ascorbic acid on absorption and first pass metabolism of isoniazid in rats. Chem Pharmaceut Bull (Tokyo) 39:445–448

    Article  Google Scholar 

  21. Banu Rekha VV, Balasubramaninan R, Swaminathan S, Ramachandran R, Rahman F, Sundaram V, Thyagarajan K, Selvakumar N, Adhilakshmi AR, Iliyas S, Narayanan PR (2007) Sputum conversion at the end of intensive phase of category-I regimen in the treatment of pulmonary tuberculosis patients with diabetes mellitus or HIV infection: an analysis of risk factors. Indian J Med Res 126:452–458

    CAS  PubMed  Google Scholar 

  22. Balasubramanian R, Ramanathan U, Thyagarajan K, Ramachandran R, Rajaram K, Bhaskar D, Shantharam Hariharan RS, Narayanan PR (2007) Evaluation of an intermittent six-month regimen in new pulmonary tuberculosis patients with diabetes mellitus. Indian J Tub 54:168–176

    Google Scholar 

  23. Viswanathan V, Vigneswari A, Selvan K, Satyavani K, Rajeswari R, Kapur A (2014) Effect of diabetes on treatment outcome of smear-positive pulmonary tuberculosis—a report from South India. J Diab Complic 28:162–165

    Article  Google Scholar 

  24. Alisjahbana B, Sahiratmadja E, Nelwan EJ, Purwa AM, Ahmad Y, Ottenhoff TH, Nelwan RH, Parwati I, van der Meer JW, van Crevel R (2007) The effect of type 2 diabetes mellitus on the presentation and treatment response of pulmonary tuberculosis. Clin Infect Dis 45:428–435

    Article  PubMed  Google Scholar 

  25. Dooley KE, Tang T, Golub JE, Dorman SE, Cronin W (2009) Impact of diabetes mellitus on treatment outcomes of patients with active tuberculosis. AmJTrop Med Hyg 80:634–639

    Google Scholar 

  26. Zhang Q, Xiao H, Sugawara I (2009) Tuberculosis complicated by diabetes mellitus at Shanghai Pulmonary Hospital, China. Jap J Infect Dis 62:390–391

    Google Scholar 

  27. Chang MJ, Chae J, Yun HY, Lee JI, Choi HD, Kim J, Park JS, Cho YJ, Yoon HI, Lee CT, Shin WG, Lee JH (2015) Effects of type 2 diabetes mellitus on the population pharmacokinetics of rifampicin in tuberculosis patients. Tuberculosis 95:54–59

    Article  CAS  PubMed  Google Scholar 

  28. Heysell SK, Moore JL, Keller SJ, Houpt ER (2010) Therapeutic drug monitoring for slow response to tuberculosis treatment in a state control program, Virginia, USA. Emerg Infect Dis 16:1546–1553

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The authors thank the patients who took part in the study, staff of the clinical biochemistry laboratory for blood glucose estimations, data entry operators, field investigators engaged in patient recruitment, staff at the RNTCP treatment centres in the Chennai Corporation and financial support by the United States Agency for International Development through World Health Organisation, SEARO, New Delhi, India.

Authors’ contributions

GR designed the study and developed the protocol, AKH and GR conducted the study, GR obtained regulatory approvals, AKH supervised drug estimations, VS carried out drug estimations by HPLC, LM and JL recruited study patients, VC and TK performed statistical analysis, GR drafted the manuscript and SS provided critical inputs and overall guidance.

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Authors and Affiliations

  1. Department of Biochemistry and Clinical Pharmacology, National Institute for Research in Tuberculosis, Mayor Sathyamoorthy Road, Chetpet, Chennai, 600 031, India

    A K Hemanth Kumar, V Chandrasekaran, T Kannan, V Sudha, Soumya Swaminathan & Geetha Ramachandran

  2. State TB Officer, Chennai, Tamil Nadu, India

    A Lakshmi Murali

  3. District TB Officer, Chennai, India

    J Lavanya

Authors
  1. A K Hemanth Kumar
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  2. V Chandrasekaran
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  3. T Kannan
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  4. A Lakshmi Murali
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  5. J Lavanya
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  6. V Sudha
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  7. Soumya Swaminathan
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  8. Geetha Ramachandran
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Corresponding author

Correspondence to Geetha Ramachandran.

Ethics declarations

The study commenced after obtaining approval from the Institutional Ethics Committee of the National Institute for Research in Tuberculosis (NIRT).

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Kumar, A.K.H., Chandrasekaran, V., Kannan, T. et al. Anti-tuberculosis drug concentrations in tuberculosis patients with and without diabetes mellitus. Eur J Clin Pharmacol 73, 65–70 (2017). https://doi.org/10.1007/s00228-016-2132-z

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  • DOI: https://doi.org/10.1007/s00228-016-2132-z

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