• Zvetanka Dobreva Zhivkova Faculty of Pharmacy, Medical University of Sofia
  • Irini Doytchinova Faculty of Pharmacy, Medical University of Sofia


Objective: Drug half-life (t1/2) is one of the key pharmacokinetic parameters for establishment of dosing regimen. Surprisingly, the relationship between the chemical structure and t1/2 is still poorly explored. The aim of the present study is to derive quantitative structure – pharmacokinetic relationships (QSPkRs) for t1/2 of acidic drugs.

Methods: The dataset consisted of 142 molecules which were described with 187 structural and physicochemical descriptors. A three step variable selection procedure was applied to identify the most reliable descriptors. QSPkR modeling was performed using multivariate regression analysis (MLR).

Results: A number of sound and robust QSPkR models were derived. The predictive ability of the models was tested by internal and external validation procedure. The most frequently emerged descriptors were used for construction of a consensus model for t1/2 prediction. The model is statistically significant (explained variance 0.688) and predictive (cross validation correlation coefficient 0.600, mean fold error of prediction 2.06, accuracy 61%). It reveals the main structural features affecting t1/2. A short check list was proposed determining the cutoff between short half life (t1/2 < 1 h) and long half life (t1/2 > 24 h) drugs.

Conclusion: The presence of a sulfonyl or phosphonate groups, non-polar substituents at aromatic carbon, 9- or 10-member ring system and donor-acceptor pair separated by 9 skeletal bonds contribute to prolongation of t1/2, while the presence of methane group, polar substituents at aromatic carbon and 7-member ring system affect negatively t1/2.


Keywords: Computational ADME, Half-life prediction, In silico modeling, QSPkR, MLR, Acidic drugs.


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1. Van der Waterbeemd H, Gifford E. ADMET in silico modeling: towards prediction paradise? Nat Rev/Drug Discovery 2000;2:192-204.
2. Kola L, Landis J. Can the pharmaceutical industry reduce attrition rates? Nat Rev/Drug Discovery 2004;3:711-5.
3. Ekins S, Waller CI, Swaan PW, Cruciani G, Wrighon SA, Wikel JH. Progress in prediction human ADME parameters in silico. J Pharmacol Toxicol Methods 2000;44:251-72.
4. Boobis A, Gundert-Remy U, Kremers P, Macheras P, Pelkonen O. In silico prediction of ADME and pharmacokinetics. Report of an expert meeting organized by COST B15. Eur J Pharm Sci 2002;17:183-93.
5. Butina D, Segall MD, Frankcombe K. Predicting ADME properties in silico: methods and models. 2002;DDT7:S83-S88.
6. Yamashita F, Hashida M. In silico approaches for predicting ADME properties of drugs. Drug Metab Pharmacokinet 2004;19:327-38.
7. Mager DE. Quantitative structure pharmacokinetic/ pharmacodynamic relationships. Adv Drug Deliv Res 2006;58:1326-56.
8. Chohan KK, Paine SW, Waters NJ. Advancements in predictive in silico models for ADME. Curr Chem Biol 2008;2:215-28.
9. Wang J, Hou T. Recent advances on in silico modeling. In: Wheeler RA, editor. Annual reports in Computational chemistry, Vol. 5. Amsterdam, San Diego: Elsevier; 2009. p. 102-27.
10. Toutain PL, Bousquet-Melou A. Plasma terminal half-life. J Vet Pharmacol Therap 2004;27:427-39.
11. Obach RS, Baxter JG; Liston TE, Silber BM, Jones BC, McIntyre F, et al. The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data. J Pharmacol Exp Therap 1997;283(1):6-58.
12. Madden JC. In silico approaches for predicting ADME properties. In: Puzyn T, Leszczynski J, Cronin MTD, editors. Recent advances in QSAR studies. Dordrecht, Heidelberg, London, New York: Springer Science + Business Media BV; 2010. p. 283-304.
13. Di L, Feng B, Goosen TC, Lay Y, Steyn SJ, Varma MV, et al. A perspective on the prediction of drug pharmacokinetics and disposition in drug research and development. Drug Metab Dispos 2013;41(12):1975-93.
14. Berezhkovskiy LM. Prediction of drug terminal half-life and terminal volume of distribution after intravenous dosing based on drug clearance, steady state volume of distribution, and physiological parameters of the body. J Pharm Sci 2013;102 (2):761-71.
15. Hockings N, Ajayi AA, Reid JL. Age and the pharmacokinetics of the angiotensin converting enzyme inhibitors enalapril and enalaprilat. Br J Clin Pharmacol 1986;21:341-8.
16. Paul Y, Parle M, Dhake AS, Singh B. In silico quantitative strructure – pharmacokinetic relationships for elimination half life of fluoroquinolones. Asian J Chem 2009;21 (7):5483-7.
17. Paul Y, Aman Singla P, Singh B. In silico quantitative structure – pharmacokinetic relationship modeling on antidiabetic drugs: half life. Int J Chem Sci 2013;11(1):177-85.
18. Zhivkova Z, Doytchinova I. Prediction of steady state volume of distribution of acidic drugs by quantitative structure-pharmacokinetics relationships. J Pharm Sci 2012;101 (3):1253-66.
19. Zhivkova Z, Doytchinova I. Quantitative structure – plasma protein binding relationships of acidic drugs. J Pharm Sci 2012;101(12):4627-41.
20. Zhivkova Z, Doytchinova I. Quantitative structure – clearance relationships of acidic drugs. Mol Pharmac 2013;10:3758-68.
21. Obach RS, Lombardo F, Waters NJ. Trend analysis of a database of intravenous pharmacokinetic parameters in humans for 670 drug compounds. Drug Metab Dispos 2008;36 (7):1385-405.
22. http: /www. drigbank. ca.
23. http: /www. chemicalbook. com.
24. Davies NM, Takimoto JK, Brocks DR, Yanez JA. Multiple peaking phenomena in pharmacokinetic disposition. Clin Pharmacokinet 2010;49 (6):351-77.
25. Newton PN, Barnes KI, Smith PJ, Evans AC, Chierakul W, Ruangveerayuth R, et al. The pharmacokinetics of intravenous artesunate in adults with severe falciparum malaria. Eur J Clin Pharmacol 2006;62:1003-9.
26. Bertler A, Lindgren S, Magnusson J-O, Malmgren H. Pharmacokinetics of chlorazepate after intravenous and intramuscular administration Psychopharmacol 1983;80 (3):236-9.
27. Barza M, Weinstein L. Pharmacokinetics of the penicillins in man. Clin Pharmacokinet 1976;1:297-308.
28. Foulds G, Stankewich JP, Marshall DC, O’Brien MM, Hayes SL, Weidler DJ, et al. Pharmacokinetics of sulbactam in humans. Antimicrob Agents Chemother 1983;23 (5):692-9.
29. Jungbluth GL, Cooper DL, Doyle GD, Chrudzik GM, Jusko WJ. Pharmacokinetics of ticarcillin and clavulanic acid (timentin) in relation to renal function. Antimicrob Agents Chemother 1986;30 (6):896-900.
30. Watanabe T, Kusihara H, Maeda K, Kanamuru H, Saito Y, Hu Z, Sugyiama Y. Investigation of the rate-limiting process in the hepatic elimination of HMG-CoA reductase inhibitors in rats and humans. Drug Metab Dispos 2010;38 (2):215-22.
31. Terhaag B, Hermann U. Biliary elimination of indomethacin in man. Eur J Clin Pharmacol 1986;29 (6):691-5.
32. Huber R, Hartmann M, Bliesash H, Luechmann R, Steinijans VW, Zech K. Pharmacokinetics of pantoprazole in man. Int J Clin Pharmacol Ther 1996;34 (1 Supl. ):7-16.
33. Wienen W, Entzeroth M, Van Meel JCA, Stangier J, Buscj U, Ebner T, et al. A review on telmisartan: a novel, long acting angiotensin II-receptor antagonist. Cardiovasc Ther 2000;18 (2):127-54.
34. Benincosa LJ, Aidet PR, Lundberg D, Zariffa N, Jorkasky DK. Pharmacokinetics and absolute bioavailability of epristeride in healthy male subjects. Biopharm Drug Dispos 1996;17 (3):249-58.
35. Devissaguet JP, Ammoury N, Devissaguet M, Perret L. Pharmacokinetics of perindopril and its metabolites in healthy volunteers. Fundam Clin Pharmacol 1990;4 (2):175-89.
36. Rolan PE, Mercer AJ, Tate E, Benjamin I, Posner J. Disposition of atovaquone in humans. Antimicrob Agents Chemother 1997;41(6):1319-21.
37. McFadyen RJ, Meredith PA, Elliott HL. Enalapril clinical pharmacokinetics and pharmacodynamic relationships. An overview. Clin Pharmacokinet 1993;25 (4):274-82.
38. Port RE, Daniel B, Ding RW, Herrmann R. Relative importance of dose, body surface area, sex, and age for 5-flurouracil clearance. Oncology 1991;48:277-81.
39. Lo MW, Goldberg MR, McCrea JB, Lu H, Furtek CI, Bjornsson TD. Pharmacokinetics of losartan, an angiotensin II receptor antagonist, and its active metabolite EXP3174 in humans. Clin Pharmacol Therap 1995;58:641-9.
40. Dockens RC, Santone KS, Mitroka JG, Morrison RA, Jemal M, Greene DS, et al. Disposition of radiolabeled ifetroban in rats, dogs, monkeys, and humans. Drug Metab Dispos 2000;28:973-80.
41. Tempero KF, Cirillo VJ, Steelman SL. Diflunisal: a review of pharmacokinetics and pharmacodynamic properties, drug interactions, and special tolerability studies in humans. Br J Clin Pharmacol 1977;4:31S-6S.
42. Nuernberg B, Koehler G, Brune K. Pharmacokinetics of diflunisal in patients. Clin Pharmacokinet 1991;20 (1):81-9.
43. Shon JH, Yoon YR, Kim MJ, Kim KA, Lim YC, Liu KH, et al. Chlorpropamide 2-hydroxylation is catalysed by CYP2C9 and CYP2C19 in vitro: chlorpropamide disposition is influenced by CYP2C9, but not by CYP2C19 genetic polymorphism. Br J Clin Pharmacol 2005;59 (5):552–63.
44. Tang BK, Inaba T, Kalow W. N-hydroxylation of pentobarbital in man. Drug Metab Dispos 1977;5:71-4.
45. Nelson E, Powell JR, Conrad K, Likes K, Byers J, Baker S, et al. Phenobarbital pharmacokinetics an bioavailability in adults. J Clin Pharmacol 1982;22(2-3):141-8.
46. Jenkings AJ. Pharmacokinetics of specific drugs. In: Karch SB, editor. Pharmacokinetics and pharmacodynamics of abused drugs. CRC Press: Taylor and Francis Group; 2008. p. 26-64.
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How to Cite
Zhivkova, Z. D., and I. Doytchinova. “IN SILICO QUANTITATIVE STRUCTURE – PHARMACOKINETIC RELATIONSHIP MODELING ON ACIDIC DRUGS: HALF LIFE”. International Journal of Pharmacy and Pharmaceutical Sciences, Vol. 6, no. 9, 1, pp. 283-9,
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