Human absorption, distribution, metabolism and excretion properties of drug molecules: A plethora of approaches

British Journal of Clinical Pharmacology

Volumn 78, Issue 6, 2014, Pages 1185-1200

  Beaumont, Claire ^a   Young, Graeme C ^a   Cavalier, Tom ^b   Young, Malcolm A ^b  

^a GLAXOSMITHKLINE   (United Kingdom)

^b GLAXOSMITHKLINE   (United States)

Author keywords

Investigational drugs; Metabolism; Pharmacokinetics; Radioactive tracers

Indexed keywords

DRUG; CARBON;

ARTICLE; COMPARATIVE STUDY; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG DISTRIBUTION; DRUG EXCRETION; DRUG METABOLISM; DRUG MICRODOSE; HUMAN; IN VITRO STUDY; IN VIVO STUDY; LIQUID CHROMATOGRAPHY; MASS SPECTROMETRY; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; RADIATION DOSE; VOLUME OF DISTRIBUTION; PHARMACOKINETICS; TANDEM MASS SPECTROMETRY; TISSUE DISTRIBUTION;

CARBON RADIOISOTOPES; CHROMATOGRAPHY, LIQUID; HUMANS; MAGNETIC RESONANCE SPECTROSCOPY; PHARMACOKINETICS; TANDEM MASS SPECTROMETRY; TISSUE DISTRIBUTION;

EID: 84918826010     PISSN: 03065251     EISSN: 13652125     Source Type: Journal    
DOI: 10.1111/bcp.12468     Document Type: Article

References (54)

1. FDA Guidance for Industry. Safety testing of drug metabolites. 2008. Available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory Information/Guidances/ucm079266.pdf2008 (last accessed 24 June 2014).
2. ICH Topic M3(R2) on non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for pharmaceuticals. 2009. Available at http://www.ema .europa.eu/docs/en-GB/document-library/Scientific-guideline/2009/09/WC500002720.pdf (last accessed 24 June 2014).
3. ICH guideline M3 (R2)-questions and answers. 2012. Available at http://www.ema.europa.eu/docs/en-GB/document-library/Other/2011/07/WC500109298.pdf (last accessed 24 June 2014).
4. Penner N, Klunk LJ, Prakash C. Human radiolabeled mass balance studies: objectives, utilities and limitations. Biopharm Drug Dispos 2009; 30: 185-203.
5. Roffey SJ, Obach RS, Gedge JI, Smith DA. What is the objective of the mass balance study? A retrospective analysis of data in animal and human excretion studies employing radiolabeled drugs. Drug Metab Rev 2007; 39: 17-43.
6. Rowland M. Microdosing: a critical assessment of human data. J Pharm Sci 2012; 101: 4067-74.
7. Lappin G, Stevens L. Biomedical accelerator mass spectrometry: recent applications in metabolism and pharmacokinetics. Expert Opin Drug Metab Toxicol 2008; 4: 1021-33.
8. Dear GJ, Beaumont C, Roberts A, Squillaci B, Thomas S, Nash M, Fraser D. Approaches for the rapid identification of drug metabolites in early clinical studies. Bioanal 2011; 3: 197-213.
9. Gao H, Obach RS. Addressing MIST (Metabolites in Safety Testing): bioanalytical approaches to address metabolite exposures in humans and animals. Curr Drug Metab 2011; 12: 578-86.
10. Nedderman ANR, Dear GJ, North S, Obach RS, Higton D. From definition to implementation: a cross-industry perspective of past, current and future MIST strategies. Xenobiotica 2011; 41: 605-22.
11. Ramanathan R, Josephs JL, Jemal M, Arnold M, Humphreys WG. Novel MS solutions inspired by MIST. Bioanalysis 2010; 2: 1291-313.
12. Guiney WJ, Beaumont C, Thomas SR, Robertson DC, McHugh SM, Koch A, Richards D. Use of Entero-Test, a simple approach for non-invasive clinical evaluation of the biliary disposition of drugs. Br J Clin Pharmacol 2011; 72: 133-42.
13. Poulin P, Jones HM, Jones RD, Yates JWT, Gibson CR, Chien JY, Ring BJ, Adkison KK, He H, Vuppugalla R, Marathe P, Fischer V, Dutta S, Sinha VK, Björnsson T, Lavé T, Ku MS. PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 1: goals, properties of the PhRMA dataset, and comparison with literature datasets. J Pharm Sci 2011; 100: 4050-73.
14. Jones RD, Jones HM, Rowland M, Gibson CR, Yates JWT, Chien JY, Ring BJ, Adkison KK, Ku MS, He H, Vuppugalla R, Marathe P, Fischer V, Dutta S, Sinha VK, Björnsson T, Lavé T, Poulin P. PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 2: comparative assessment of prediction methods of human volume of distribution. J Pharm Sci 2011; 100: 4074-89.
15. Ring BJ, Chien JY, Adkison KK, Jones HM, Rowland M, Jones RD, Yates JWT, Ku MS, Gibson CR, He H, Vuppugalla R, Marathe P, Fischer V, Dutta S, Sinha VK, Björnsson T, Lavé T, Poulin P. PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 3: comparative assessement of prediction methods of human clearance. J Pharm Sci 2011; 100: 4090-110.
16. Vuppugalla R, Marathe P, He H, Jones RDO, Yates JWT, Jones HM, Gibson CR, Chien JY, Ring BJ, Adkison KK, Ku MS, Fischer V, Dutta S, Sinha VK, Björnsson T, Lavé T, Poulin P. PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 4: prediction of plasma concentration-time profiles in human from in vivo preclinical data by using the Wajima approach. J Pharm Sci 2011; 100: 4111-26.
17. Poulin P, Jones RDO, Jones HM, Gibson CR, Rowland M, Chien JY, Ring BJ, Adkison KK, Ku MS, He H, Vuppugalla R, Marathe P, Fischer V, Dutta S, Sinha VK, Björnsson T, Lavé T, Yates JWT. PHRMA CPCDC initiative on predictive models of human pharmacokinetics, part 5: prediction of plasma concentration-time profiles in human by using the physiologically-based pharmacokinetic modeling approach. J Pharm Sci 2011; 100: 4127-57.
18. Kostewicz ES, Aarons L, Bergstrand M, Bolger MB, Galetin A, Hatley O, Jamei M, Lloyd R, Pepin X, Rostami-Hodjegan A, Sjögren E, Tannergren C, Turner DB, Wagner C, Weitschies W, Dressman J. PBPK models for the prediction of in vivo performance of oral dosage forms. Eur J Pharm Sci 2014; 57: 300-21.
19. Lappin G, Noveck R, Burt T. Microdosing and drug development: past, present and future. Expert Opin Drug Metab Toxicol 2013; 9: 817-34.
20. Xu X, Jiang H, Christopher LJ, Shen JX, Zeng J, Arnold ME. Sensitivity based analytical approaches to support human absolute bioavailability studies. Bioanalysis 2014; 6: 497-504.
21. Ostenfeld T, Beaumont C, Bullman J, Beaumont M, Jeffrey P. Human microdose evaluation of the novel EP1 receptor antagonist GSK269984A. Br J Clin Pharmacol 2012; 74: 1033-44.
22. Cahn A, Hodgson S, Wilson R, Robertson J, Watson J, Beerahee M, Hughes SC, Young G, Graves R, Hall D, van Marle S, Solari R. Safety, tolerability, pharmacokinetics and pharmacodynamics of GSK2239633, a CC-chemokine receptor 4 antagonist, in healthy male subjects: results from an open-label and from a randomised study. BMC Pharmacol Toxicol 2013; 14: 14.
23. Lappin G, Kuhnz W, Jochemsen R, Kneer J, Chaudhary A, Oosterhuis B, Drijfhout WJ, Rowland M, Garner RC. Use of microdosing to predict pharmacokinetics at the therapeutic dose: experience with 5 drugs. Clin Pharmacol Ther 2006; 80: 203-15.
24. Lappin G, Shishikura Y, Jochemsen R, Weaver RJ, Gesson C, Houston JB, Oosterhuis B, Bjerrum OJ, Grynkiewicz G, Alder J, Rowland M, Garner C. Comparative pharmacokinetics between a microdose and therapeutic dose for clarithromycin, sumatriptan, propafenone, paracetamol (acetaminophen) and phenobarbital in human volunteers. Eur J Pharm Sci 2011; 43: 141-50.
25. Mahar KM, Sehon C, Tai G, Haws T, Howe D, Young G, Danoff T. Comparison of a GSK706769 microdose CYP3A4 drug-drug interaction study with a previous pharmacological dose study. American College of Clinical Pharmacology, Annual Meeting September 23rd-25th, San Diego, California. 2012; abstract #1393294.
26. Harrison A, Gardner I, Hay T, Dickins M, Beaumont K, Phipps A, Purkins L, Allan G, Christian R, Duckworth J, Gurrell I, Kempshall S, Savage M, Seymour M, Simpson M, Taylor L, Turnpenny P. Case studies addressing human pharmacokinetic uncertainty using a combination of pharmacokinetic simulation and alternative first in human paradigms. Xenobiotica 2012; 42: 57-74.
27. Vogel JS, Turteltaub KW. Accelerator mass spectrometry as a bioanalytical tool for nutritional research. Adv Exp Med Biol 1998; 445: 397-410.
28. Jiang H, Zeng J, Li W, Bifano M, Gu H, Titsch C, Easter J, Burrell R, Kandoussi H, Aubry AF, Arnold M. Practical and efficient strategy for evaluating oral absolute bioavailability with an intravenous microdose of a stable isotopically-labeled drug using a selected reaction monitoring mass spectrometry assay. Anal Chem 2012; 84: 10031-7.
29. Sarapa N, Hsyu PH, Lappin G, Garner RC. The application of accelerator mass spectrometry to absolute bioavailability studies in humans: simultaneous administration of an intravenous microdose of 14C-nelfinavir mesylate solution and oral nelfinavir to healthy volunteers. J Clin Pharmacol 2005; 45: 1198-205.
30. Stevens LA, Evans P, Dueker SR, Lohstroh PN, Giacomo J, Tu D, Shen Z, Yeh L, Ong V, Densel M, Rowlings C, Quart B. Microdose and microtracer intravenous pharmacokinetics of RDEA806 in healthy subjects. Clin Pharmacol Ther 2009; 85: S24-5.
31. Wu A, Stevens LA, Savant I, Wang X, Laskin OL. Absolute bioavailability of CC-11050, a low water soluble NCE using an i.v. microdose of [14C]-CC-11050 solution concomitantly with an oral unlabelled dose. Clin Pharmacol Ther 2010; 87: S88.
32. Daley-Yates P, Norris V, Ambery C, Preece A. Early clinical evaluation of a novel 5-lipoxygenase activating protein (FLAP) inhibitor (GSK2190915A). Pharmacokinetics, bioavailability and dose form selection: influence of age, food, drug interactions and regional absorption (LPA112071, LPA112362, LPA114604). Proceedings of the British Pharmacological Society, BPS Winter Meeting. 2012. Available at http://www.pa2online.org/abstract/abstract .jsp?abid=30851&author =preece&cat=-1&period=-1 (last accessed 30 November 2013).
33. Vasist Johnson LS, Young MA, Stevens LA, Cozens SJ, Collier J, Robertson DC, Dukes GE. A microtracer study of GSK962040, a motilin receptor agonist, to support dosing regimens in the critical care setting. Clin Pharmacol Ther 2012; 91: S80.
34. Schwab D, Portron A, Backholer Z, Lausecker B, Kawashima K. A novel double-tracer technique to characterize absorption, distribution, metabolism and excretion (ADME) of [14C]tofogliflozin after oral administration and concomitant intraveous microdose administration of [13C]tofogliflozin in humans. Clin Pharmacokinet 2013; 52: 463-73.
35. Leonowens C, Pendry C, Bauman J, Young GC, Ho M, Henriquez F, Fang L, Morrison RA, Orford K, Ouellet D. Concomitant oral and intravenous pharmacokinetics of trametinib, a MEK inhibitor, in subjects with solid tumours. Br J Clin Pharmacol 2014; 78: 524-32.
36. Dear GJ, Roberts AD, Beaumont C, North SE. Evaluation of preparative high performance liquid chromatography and cryoprobe-nuclear magnetic resonance spectroscopy for the early quantitative estimation of drug metabolites in human plasma. J Chromatogr B 2008; 876: 182-90.
37. Hop CECA, Wang Z, Chen Q, Kwei G. Plasma-pooling methods to increase throughput for in vivo pharmacokinetic screening. J Pharm Sci 1998; 87: 901-3.
38. Vishwanathan K, Babalola K, Wang J, Espina R, Yu L, Adedoyin A, Talaat R, Mutlib A, Scatina J. Obtaining exposures of metabolites in preclinical species through plasma pooling and quantitative NMR: addressing metabolites in safety testing (MIST) guidance without using radiolabeled compounds and chemically synthesized metabolite standards. Chem Res Toxicol 2009; 22: 311-22.
39. Yu C, Chen CL, Gorycki FL, Neiss TG. A rapid method for quantitatively estimating metabolites in human plasma in the absence of synthetic standards using a combination of liquid chromatography/mass spectrometry and radiometric detection. Rapid Commun Mass Spectrom 2007; 21: 497-502.
40. Ismail IM, Dear GJ, Roberts AD, Plumb RS, Ayrton J, Sweatman BC, Bowers GD. N-O glucuronidation: a major human metabolic pathway in the elimination of two novel anticonvulsant drug candidates. Xenobiotica 2002; 32: 29-43.
41. Ghibellini G, Johnson BM, Kowalsky RJ, Heizer WD, Brouwer KLR. A novel method for the determination of biliary clearance in humans. AAPS J 2004; 6: 45-52.
42. Ghibellini G, Leslie EM, Brouwer KLR. Methods to evaluate biliary excretion of drug in human: an updated review. Mol Pharm 2006; 3: 198-211.
43. Cheng H, Schwartz MS, Vickers S, Gilbert JD, Amin RD, Depuy B, Liu L, Rogers JD, Pond SM, Duncan CA, Olah TV, Bayne WF. Metabolic disposition of simvastatin in patients with T-tube drainage. Drug Metab Dispos 1994; 22: 139-42.
44. Vickers S, Duncan CA, Vyas KP, Kari PH, Arison B, Prakash SR, Ramjit HG, Pitzenberger SM, Stokker G, Duggan DE. In vitro and in vivo biotransformation of simvastatin, an inhibitor of HMG CoA reductase. Drug Metab Dispos 1990; 18: 476-83.
45. Bloomer JC, Nash M, Webb A, Miller BE, Lazaar AL, Beaumont C, Guiney WJ. Assessment of potential drug interactions by characterization of human drug metabolism pathways using non-invasive bile sampling. Br J Clin Pharmacol 2013; 75: 488-96.
46. Hughes SC, Shardlow PC, Hollis FJ, Scott RJ, Motivaras DS, Allen A, Rousell VM. Metabolism and disposition of fluticasone furoate, an enhanced-affinity glucocorticoid, in humans. Drug Metab Dispos 2008; 36: 2337-44.
47. Harrell AW, Siederer SK, Bal J, Patel NH, Young GC, Felgate CC, Pearce SJ, Roberts AD, Beaumont C, Emmons AJ, Pereira AI, Kempsford RD. Metabolism and disposition of vilanterol, a long-acting ?2-adrenoreceptor agonist for inhalation use in humans. Drug Metab Dispos 2013; 41: 89-100.
48. Prakash C, Li Z, Orlandi C, Klunk L. Assessment of Exposure of Metabolites in preclinical species and humans at steady state from the singl-dose radiolabelled absorption, distribution, metabolism, and excretion studies: a case study. Drug Metab Dispos 2012; 40: 1308-20.
49. Dave M, Nash M, Young GC, Ellens H, Magee M, Roberts AD, Taylor MA, Greenhill RW, Boyle GW. Disposition and metabolism of darapladib, a lipoprotein-associated phospholipase A2 inhibitor, in humans. Drug Metab Dispos 2014; 42: 415-30.
50. Young GC, Ellis WJ. AMS in drug development in GSK. Nucl Instrum Methods Phys Res B 2007; 259: 752-7.
51. Beumer JH, Beijnen JH, Schellens JHM. Mass balance studies, with a focus on anticancer drugs. Clin Pharmacokinet 2006; 45: 33-58.
52. Deng Y, Sychterz C, Suttle AB, Dar MM, Bershas D, Negash K, Qian Y, Chen EP, Gorycki PD, Ho MYK. Bioavailability, metabolism and disposition of oral pazopanib in patients with advanced cancer. Xenobiotica 2013; 43: 443-53.
53. Bershas DA, Ouellet D, Mamaril-Fishman DB, Nebot N, Carson SW, Blackman SC, Morrison RA, Adams JL, Jurusik KE, Knecht DM, Gorycki PD, Richards-Peterson LE. Metabolism and disposition of oral dabrafenib in cancer patients: proposed participation of aryl nitrogen in carbon-carbon bond cleavage via decarboxylation following enzymatic oxidation. Drug Metab Dispos 2013; 41: 2215-24.
54. Ho MYK, Morris MJ, Pirhalla JL, Bauman JW, Pendry B, Orford KW, Morrison RA, Cox DS. Trametinib, a first-in-class oral MEK inhibitor mass balance study with limited enrolment of two male subjects with advanced cancers. Xenobiotica 2014; 44: 352-68.