1932

Abstract

Pharmacokinetic parameters of selective probe substrates are used to quantify the activity of an individual pharmacokinetic process (PKP) and the effect of perpetrator drugs thereon in clinical drug–drug interaction (DDI) studies. For instance, oral caffeine is used to quantify hepatic CYP1A2 activity, and oral dagibatran etexilate for intestinal P-glycoprotein (P-gp) activity. However, no probe substrate depends exclusively on the PKP it is meant to quantify. Lack of selectivity for a given enzyme/transporter and expression of the respective enzyme/transporter at several sites in the human body are the main challenges. Thus, a detailed understanding of the role of individual PKPs for the pharmacokinetics of any probe substrate is essential to allocate the effect of a perpetrator drug to a specific PKP; this is a prerequisite for reliably informed pharmacokinetic models that will allow for the quantitative prediction of perpetrator effects on therapeutic drugs, also in respective patient populations not included in DDI studies.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pharmtox-010818-021909
2019-01-06
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/pharmtox/59/1/annurev-pharmtox-010818-021909.html?itemId=/content/journals/10.1146/annurev-pharmtox-010818-021909&mimeType=html&fmt=ahah

Literature Cited

  1. 1.  Fuhr U, Jetter A, Kirchheiner J 2007. Appropriate phenotyping procedures for drug metabolizing enzymes and transporters in humans and their simultaneous use in the “cocktail” approach. Clin. Pharmacol. Ther. 81:2270–83In part a previous version of the present article, still worth reading.
    [Google Scholar]
  2. 2.  McDonnell PJ, Jacobs MR 2002. Hospital admissions resulting from preventable adverse drug reactions. Ann. Pharmacother. 36:91331–36
    [Google Scholar]
  3. 3.  Hakkarainen KM, Gyllensten H, Jonsson AK, Andersson Sundell K, Petzold M, Hagg S 2014. Prevalence, nature and potential preventability of adverse drug events—a population-based medical record study of 4970 adults. Br. J. Clin. Pharmacol. 78:1170–83
    [Google Scholar]
  4. 4.  Obreli-Neto PR, Nobili A, de Oliveira Baldoni A, Guidoni CM, de Lyra Junior DP et al. 2012. Adverse drug reactions caused by drug-drug interactions in elderly outpatients: a prospective cohort study. Eur. J. Clin. Pharmacol. 68:121667–76
    [Google Scholar]
  5. 5.  Chang F, O'Hare AM, Miao Y, Steinman MA 2015. Use of renally inappropriate medications in older veterans: a national study. J. Am. Geriatr. Soc. 63:112290–97
    [Google Scholar]
  6. 6.  Backman JT, Kivistö KT, Olkkola KT, Neuvonen PJ 1998. The area under the plasma concentration-time curve for oral midazolam is 400-fold larger during treatment with itraconazole than with rifampicin. Eur. J. Clin. Pharmacol. 54:153–58
    [Google Scholar]
  7. 7.  Magro L, Moretti U, Leone R 2012. Epidemiology and characteristics of adverse drug reactions caused by drug-drug interactions. Expert Opin. Drug Saf. 11:183–94
    [Google Scholar]
  8. 8.  Dechanont S, Maphanta S, Butthum B, Kongkaew C 2014. Hospital admissions/visits associated with drug-drug interactions: a systematic review and meta-analysis. Pharmacoepidemiol. Drug Saf. 23:5489–97
    [Google Scholar]
  9. 9.  Subramanian A, Adhimoolam M, Kannan S 2018. Study of drug-drug interactions among the hypertensive patients in a tertiary care teaching hospital. Perspect. Clin. Res. 9:19–14
    [Google Scholar]
  10. 10. U.S. Food Drug Admin. 2017. Clinical drug interaction studies—study design, data analysis, and clinical implications: guidance for industry Draft Guid., US Dep. Health Hum. Serv. Rockville, MD: https://www.fda.gov/downloads/drugs/guidances/ucm292362.pdf
  11. 11. Eur. Med. Agency. 2012. Guideline on the investigation of drug interactions Rep. CPMP/EWP/560/95/Rev. 1 Corr. 2** Eur. Med. Agency London:
  12. 12.  Weisiger RA 1985. Dissociation from albumin: a potentially rate-limiting step in the clearance of substances by the liver. PNAS 82:51563–67
    [Google Scholar]
  13. 13. US Food Drug Admin. 2017. In vitro metabolism- and transporter-mediated drug-drug interaction studies: guidance for industry Draft Guid., US Dep. Health Hum. Serv. Rockville, MD: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM581965.pdf
  14. 14.  Sager JE, Yu J, Ragueneau-Majlessi I, Isoherranen N 2015. Physiologically based pharmacokinetic (PBPK) modeling and simulation approaches: a systematic review of published models, applications, and model verification. Drug Metab. Dispos. 43:111823–37
    [Google Scholar]
  15. 15.  Min JS, Bae SK 2017. Prediction of drug-drug interaction potential using physiologically based pharmacokinetic modeling. Arch. Pharm. Res. 40:121356–79
    [Google Scholar]
  16. 16.  Fuhr U, Weiss M, Kroemer HK, Neugebauer G, Rameis H et al. 1996. Systematic screening for pharmacokinetic interactions during drug development. Int. J. Clin. Pharmacol. Ther. 34:4139–51
    [Google Scholar]
  17. 17.  Mao J, Martin I, McLeod J, Nolan G, van Horn R et al. 2017. Perspective: 4β-hydroxycholesterol as an emerging endogenous biomarker of hepatic CYP3A. Drug Metab. Rev. 49:118–34
    [Google Scholar]
  18. 18.  Tay-Sontheimer J, Shireman LM, Beyer RP, Senn T, Witten D et al. 2014. Detection of an endogenous urinary biomarker associated with CYP2D6 activity using global metabolomics. Pharmacogenomics 15:161947–62
    [Google Scholar]
  19. 19.  Fuhr U 2018. Pharmacokinetic phenotyping to predict drug-drug interactions: time to divorce the hybrid concept of simultaneous mechanistic-based and exposure-based assessment. Clin. Pharmacol. Ther. 103:142–42
    [Google Scholar]
  20. 20.  Gazzaz M, Kinzig M, Schaeffeler E, Jübner M, Hsin C et al. 2018. Drinking ethanol has few acute effects on CYP2C9, CYP2C19, NAT2 and P-glycoprotein activities but somewhat inhibits CYP1A2, CYP2D6 and intestinal CYP3A: so what?. Clin. Pharmacol. Ther. In press
  21. 21.  Derungs A, Donzelli M, Berger B, Noppen C, Krahenbuhl S, Haschke M 2016. Effects of cytochrome P450 inhibition and induction on the phenotyping metrics of the Basel cocktail: a randomized crossover study. Clin. Pharmacokinet. 55:179–91
    [Google Scholar]
  22. 22.  Ma JD, Nafziger AN, Bertino JS 2012. Validating phenotyping cocktails: More work needs to be done. J. Clin. Pharmacol. 52:111772–73
    [Google Scholar]
  23. 23.  Momper JD, Tsunoda SM, Ma JD 2016. Evaluation of proposed in vivo probe substrates and inhibitors for phenotyping transporter activity in humans. J. Clin. Pharmacol. 56:S82–98
    [Google Scholar]
  24. 24.  Kirwan C, MacPhee I, Philips B 2010. Using drug probes to monitor hepatic drug metabolism in critically ill patients: midazolam, a flawed but useful tool for clinical investigation of CYP3A activity?. Expert Opin. Drug Metab. Toxicol. 6:6761–71
    [Google Scholar]
  25. 25.  Berezhkovskiy LM 2012. Determination of hepatic clearance with the account of drug-protein binding kinetics. J. Pharm. Sci. 101:103936–45
    [Google Scholar]
  26. 26.  Fung KYY, Fairn GD, Lee WL 2018. Transcellular vesicular transport in epithelial and endothelial cells: challenges and opportunities. Traffic 19:15–18
    [Google Scholar]
  27. 27.  Petrovich YA, Yarema IV, Kichenko SM, Urtaev BM 2009. Study of drug transport between the blood and lymph in the predominant direction. Bull. Exp. Biol. Med. 147:3357–60
    [Google Scholar]
  28. 28.  Yadav P, McLeod VM, Nowell CJ, Selby LI, Johnston APR et al. 2018. Distribution of therapeutic proteins into thoracic lymph after intravenous administration is protein size-dependent and primarily occurs within the liver and mesentery. J. Control. Release 272:17–28
    [Google Scholar]
  29. 29.  Oswald S, Terhaag B, Siegmund W 2011. In vivo probes of drug transport: commonly used probe drugs to assess function of intestinal P-glycoprotein (ABCB1) in humans. Drug Transporters M Fromm, R Kim 403–47 Berlin: Springer
    [Google Scholar]
  30. 30.  Ma JD, Tsunoda SM, Bertino JS, Trivedi M, Beale KK, Nafziger AN 2010. Evaluation of in vivo P-glycoprotein phenotyping probes. Clin. Pharmacokinet. 49:4223–37
    [Google Scholar]
  31. 31.  Tucker GT, Houston JB, Huang SM 2001. Optimizing drug development: strategies to assess drug metabolism/transporter interaction potential—towards a consensus. Pharm. Res. 18:81071–80
    [Google Scholar]
  32. 32.  Peters SA, Jones CR, Ungell A-L, Hatley OJD 2016. Predicting drug extraction in the human gut wall: assessing contributions from drug metabolizing enzymes and transporter proteins using preclinical models. Clin. Pharmacokinet. 55:6673–96
    [Google Scholar]
  33. 33.  Yokose T, Doy M, Taniguchi T, Shimada T, Kakiki M et al. 1999. Immunohistochemical study of cytochrome P450 2C and 3A in human non-neoplastic and neoplastic tissues. Virchows Arch 434:5401–11
    [Google Scholar]
  34. 34.  Palmer CN, Coates PJ, Davies SE, Shephard EA, Phillips IR 1992. Localization of cytochrome P-450 gene expression in normal and diseased human liver by in situ hybridization of wax-embedded archival material. Hepatology 16:3682–87
    [Google Scholar]
  35. 35.  Daly AK 2006. Significance of the minor cytochrome P450 3A isoforms. Clin. Pharmacokinet. 45:113–31
    [Google Scholar]
  36. 36.  Gorski JC, Jones DR, Haehner-Daniels BD, Hamman MA, O'Mara EM, Hall SD 1998. The contribution of intestinal and hepatic CYP3A to the interaction between midazolam and clarithromycin. Clin. Pharmacol. Ther. 64:2133–43
    [Google Scholar]
  37. 37.  Koch I, Weil R, Wolbold R, Brockmöller J, Hustert E et al. 2002. Interindividual variability and tissue-specificity in the expression of cytochrome P450 3A mRNA. Drug Metab Dispos 30:101108–14
    [Google Scholar]
  38. 38.  Klein K, Zanger UM 2013. Pharmacogenomics of cytochrome P450 3A4: recent progress toward the “missing heritability” problem. Front. Genet. 4:12
    [Google Scholar]
  39. 39.  Tomalik-Scharte D, Maiter D, Kirchheiner J, Ivison HE, Fuhr U, Arlt W 2010. Impaired hepatic drug and steroid metabolism in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency. Eur. J. Endocrinol. 163:6919–24
    [Google Scholar]
  40. 40.  Thirumaran RK, Lamba JK, Kim RB, Urquhart BL, Gregor JC et al. 2012. Intestinal CYP3A4 and midazolam disposition in vivo associate with VDR polymorphisms and show seasonal variation. Biochem. Pharmacol. 84:1104–12
    [Google Scholar]
  41. 41.  Henderson CJ, McLaughlin LA, Scheer N, Stanley LA, Wolf CR 2015. Cytochrome b5 is a major determinant of human cytochrome P450 CYP2D6 and CYP3A4 activity in vivo. Mol. Pharmacol. 87:4733–39
    [Google Scholar]
  42. 42.  Sevrioukova IF, Poulos TL 2013. Understanding the mechanism of cytochrome P450 3A4: recent advances and remaining problems. Dalton Trans 42:93116–26
    [Google Scholar]
  43. 43.  Foti RS, Rock DA, Wienkers LC, Wahlstrom JL 2010. Selection of alternative CYP3A4 probe substrates for clinical drug interaction studies using in vitro data and in vivo simulation. Drug Metab. Dispos. 38:6981–87
    [Google Scholar]
  44. 44.  Kenworthy KE, Bloomer JC, Clarke SE, Houston JB 1999. CYP3A4 drug interactions: correlation of 10 in vitro probe substrates. Br. J. Clin. Pharmacol. 48:5716–27
    [Google Scholar]
  45. 45.  Benet LZ 2005. There are no useful CYP3A probes that quantitatively predict the in vivo kinetics of other CYP3A substrates and no expectation that one will be found. Mol. Interv. 5:279–83
    [Google Scholar]
  46. 46.  Heizmann P, Eckert M, Ziegler WH 1983. Pharmacokinetics and bioavailability of midazolam in man. Br. J. Clin. Pharmacol. 16:Suppl. 143S–49S
    [Google Scholar]
  47. 47.  Thummel KE, O'Shea D, Paine MF, Shen DD, Kunze KL et al. 1996. Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism. Clin. Pharmacol. Ther. 59:5491–502
    [Google Scholar]
  48. 48.  Hohmann N, Kocheise F, Carls A, Burhenne J, Haefeli WE, Mikus G 2015. Midazolam microdose to determine systemic and pre-systemic metabolic CYP3A activity in humans. Br. J. Clin. Pharmacol. 79:2278–85
    [Google Scholar]
  49. 49.  Floyd MD, Gervasini G, Masica AL, Mayo G, George AL et al. 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 13:10595–606
    [Google Scholar]
  50. 50.  Vossen M, Sevestre M, Niederalt C, Jang IJ, Willmann S, Edginton AN 2007. Dynamically simulating the interaction of midazolam and the CYP3A4 inhibitor itraconazole using individual coupled whole-body physiologically-based pharmacokinetic (WB-PBPK) models. Theor. Biol. Med. Model. 4:13
    [Google Scholar]
  51. 51.  Yu K-S, Cho J-Y, Jang I-J, Hong K-S, Chung J-Y et al. 2004. Effect of the CYP3A5 genotype on the pharmacokinetics of intravenous midazolam during inhibited and induced metabolic states. Clin. Pharmacol. Ther. 76:2104–12
    [Google Scholar]
  52. 52.  Williams JA, Ring BJ, Cantrell VE, Jones DR, Eckstein J et al. 2002. Comparative metabolic capabilities of CYP3A4, CYP3A5, and CYP3A7. Drug Metab. Dispos. 30:8883–91
    [Google Scholar]
  53. 53.  Hyland R, Osborne T, Payne A, Kempshall S, Logan YR et al. 2009. In vitro and in vivo glucuronidation of midazolam in humans. Br. J. Clin. Pharmacol. 67:4445–54
    [Google Scholar]
  54. 54.  Kim RB, Wandel C, Leake B, Cvetkovic M, Fromm MF et al. 1999. Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein. Pharm. Res. 16:3408–14
    [Google Scholar]
  55. 55.  Halama B, Hohmann N, Burhenne J, Weiss J, Mikus G, Haefeli WE 2013. A nanogram dose of the CYP3A probe substrate midazolam to evaluate drug interactions. Clin. Pharmacol. Ther. 93:6564–71An amazing example of probe drug microdosing.
    [Google Scholar]
  56. 56.  Bornemann LD, Min BH, Crews T, Rees MM, Blumenthal HP et al. 1985. Dose dependent pharmacokinetics of midazolam. Eur. J. Clin. Pharmacol. 29:191–95
    [Google Scholar]
  57. 57.  de Jonge H, de Loor H, Verbeke K, Vanrenterghem Y, Kuypers DR 2013. Impact of CYP3A5 genotype on tacrolimus versus midazolam clearance in renal transplant recipients: new insights in CYP3A5-mediated drug metabolism. Pharmacogenomics 14:121467–80
    [Google Scholar]
  58. 58.  Vanhove T, Bouillon T, de Loor H, Annaert P, Kuypers D 2017. Fexofenadine, a putative in vivo P-glycoprotein probe, fails to predict clearance of the substrate tacrolimus in renal recipients. Clin. Pharmacol. Ther. 102:6989–96
    [Google Scholar]
  59. 59.  Lee J, Chaves-Gnecco D, Amico JA, Kroboth PD, Wilson JW, Frye RF 2002. Application of semisimultaneous midazolam administration for hepatic and intestinal cytochrome P450 3A phenotyping. Clin. Pharmacol. Ther. 72:6718–28
    [Google Scholar]
  60. 60.  Frechen S, Junge L, Saari TI, Suleiman AA, Rokitta D et al. 2013. A semiphysiological population pharmacokinetic model for dynamic inhibition of liver and gut wall cytochrome P450 3A by voriconazole. Clin. Pharmacokinet. 52:9763–81An example of a semiphysiological midazolam model to improve understanding of CYP3A-based PK interaction.
    [Google Scholar]
  61. 61.  Gertz M, Harrison A, Houston JB, Galetin A 2010. Prediction of human intestinal first-pass metabolism of 25 CYP3A substrates from in vitro clearance and permeability data. Drug Metab. Dispos. 38:71147–58
    [Google Scholar]
  62. 62.  Ohno Y, Hisaka A, Suzuki H 2007. General framework for the quantitative prediction of CYP3A4-mediated oral drug interactions based on the AUC increase by coadministration of standard drugs. Clin. Pharmacokinet. 46:8681–96
    [Google Scholar]
  63. 63.  Ohno Y, Hisaka A, Ueno M, Suzuki H 2008. General framework for the prediction of oral drug interactions caused by CYP3A4 induction from in vivo information. Clin. Pharmacokinet. 47:10669–80
    [Google Scholar]
  64. 64.  Park G-J, Bae SH, Park W-S, Han S, Park M-H et al. 2017. Drug-drug interaction of microdose and regular-dose omeprazole with a CYP2C19 inhibitor and inducer. Drug Des. Dev. Ther. 11:1043–53
    [Google Scholar]
  65. 65.  Gröer C, Busch D, Patrzyk M, Beyer K, Busemann A et al. 2014. Absolute protein quantification of clinically relevant cytochrome P450 enzymes and UDP-glucuronosyltransferases by mass spectrometry-based targeted proteomics. J. Pharm. Biomed. Anal. 100:393–401
    [Google Scholar]
  66. 66.  Karam WG, Goldstein JA, Lasker JM, Ghanayem BI 1996. Human CYP2C19 is a major omeprazole 5-hydroxylase, as demonstrated with recombinant cytochrome P450 enzymes. Drug Metab. Dispos. 24:101081–87
    [Google Scholar]
  67. 67.  Kanebratt KP, Diczfalusy U, Bäckström T, Sparve E, Bredberg E et al. 2008. Cytochrome P450 induction by rifampicin in healthy subjects: determination using the Karolinska cocktail and the endogenous CYP3A4 marker 4β-hydroxycholesterol. Clin. Pharmacol. Ther. 84:5589–94
    [Google Scholar]
  68. 68.  Ogilvie BW, Yerino P, Kazmi F, Buckley DB, Rostami-Hodjegan A et al. 2011. The proton pump inhibitor, omeprazole, but not lansoprazole or pantoprazole, is a metabolism-dependent inhibitor of CYP2C19: implications for coadministration with clopidogrel. Drug Metab. Dispos. 39:112020–33
    [Google Scholar]
  69. 69.  Pauli-Magnus C, Rekersbrink S, Klotz U, Fromm MF 2001. Interaction of omeprazole, lansoprazole and pantoprazole with P-glycoprotein. Naunyn. Schmiedebergs. Arch. Pharmacol. 364:6551–57
    [Google Scholar]
  70. 70.  Ogawa R, Echizen H 2010. Drug-drug interaction profiles of proton pump inhibitors. Clin. Pharmacokinet. 49:8509–33
    [Google Scholar]
  71. 71.  Shirasaka Y, Sager JE, Lutz JD, Davis C, Isoherranen N 2013. Inhibition of CYP2C19 and CYP3A4 by omeprazole metabolites and their contribution to drug-drug interactions. Drug Metab. Dispos. 41:71414–24
    [Google Scholar]
  72. 72.  Doroshyenko O, Rokitta D, Zadoyan G, Klement S, Schläfke S et al. 2013. Drug cocktail interaction study on the effect of the orally administered lavender oil preparation silexan on cytochrome P450 enzymes in healthy volunteers. Drug Metab. Dispos. 41:5987–93
    [Google Scholar]
  73. 73.  Zadoyan G, Rokitta D, Klement S, Dienel A, Hoerr R et al. 2012. Effect of Ginkgo biloba special extract EGb 761® on human cytochrome P450 activity: a cocktail interaction study in healthy volunteers. Eur. J. Clin. Pharmacol. 68:5553–60
    [Google Scholar]
  74. 74.  Zhao W, Leroux S, Biran V, Jacqz-Aigrain E 2018. Developmental pharmacogenetics of CYP2C19 in neonates and young infants: omeprazole as a probe drug. Br. J. Clin. Pharmacol. 84:5997–1005
    [Google Scholar]
  75. 75.  Baldwin RM, Ohlsson S, Pedersen RS, Mwinyi J, Ingelman-Sundberg M et al. 2008. Increased omeprazole metabolism in carriers of the CYP2C19*17 allele; a pharmacokinetic study in healthy volunteers. Br. J. Clin. Pharmacol. 65:5767–74
    [Google Scholar]
  76. 76.  Frank D, Jaehde U, Fuhr U 2007. Evaluation of probe drugs and pharmacokinetic metrics for CYP2D6 phenotyping. Eur. J. Clin. Pharmacol. 63:4321–33
    [Google Scholar]
  77. 77.  Nakashima D, Takama H, Ogasawara Y, Kawakami T, Nishitoba T et al. 2007. Effect of cinacalcet hydrochloride, a new calcimimetic agent, on the pharmacokinetics of dextromethorphan: in vitro and clinical studies. J. Clin. Pharmacol. 47:101311–19
    [Google Scholar]
  78. 78.  Storelli F, Matthey A, Lenglet S, Thomas A, Desmeules J, Daali Y 2018. Impact of CYP2D6 functional allelic variations on phenoconversion and drug-drug interactions. Clin. Pharmacol. Ther. 104:1148–57
    [Google Scholar]
  79. 79.  Capon DA, Bochner F, Kerry N, Mikus G, Danz C, Somogyi AA 1996. The influence of CYP2D6 polymorphism and quinidine on the disposition and antitussive effect of dextromethorphan in humans. Clin. Pharmacol. Ther. 60:3295–307
    [Google Scholar]
  80. 80.  Ieiri I, Fukae M, Maeda K, Ando Y, Kimura M et al. 2012. Pharmacogenomic/pharmacokinetic assessment of a four-probe cocktail for CYPs and OATPs following oral microdosing. Int. J. Clin. Pharmacol. Ther. 50:10689–700
    [Google Scholar]
  81. 81.  Schadel M, Wu D, Otton SV, Kalow W, Sellers EM 1995. Pharmacokinetics of dextromethorphan and metabolites in humans: influence of the CYP2D6 phenotype and quinidine inhibition. J. Clin. Psychopharmacol. 15:4263–69
    [Google Scholar]
  82. 82.  Miyauchi E, Tachikawa M, Declèves X, Uchida Y, Bouillot J-L et al. 2016. Quantitative atlas of cytochrome P450, UDP-glucuronosyltransferase, and transporter proteins in jejunum of morbidly obese subjects. Mol. Pharm. 13:82631–40
    [Google Scholar]
  83. 83.  Greiner B, Eichelbaum M, Fritz P, Kreichgauer HP, von Richter O et al. 1999. The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin. J. Clin. Investig. 104:2147–53Application of suitable validation procedures for a transporter probe drug.
    [Google Scholar]
  84. 84.  He J, Yu Y, Prasad B, Chen X, Unadkat JD 2014. Mechanism of an unusual, but clinically significant, digoxin-bupropion drug interaction. Biopharm. Drug Dispos. 35:5253–63
    [Google Scholar]
  85. 85.  Martin P, Gillen M, Millson D, Oliver S, Brealey C et al. 2015. Effects of fostamatinib on the pharmacokinetics of digoxin (a P-glycoprotein substrate): results from in vitro and phase I clinical studies. Clin. Ther. 37:122811–22
    [Google Scholar]
  86. 86.  Pedersen KE, Dorph-Pedersen A, Hvidt S, Klitgaard NA, Pedersen KK 1982. The long-term effect of verapamil on plasma digoxin concentration and renal digoxin clearance in healthy subjects. Eur. J. Clin. Pharmacol. 22:2123–27
    [Google Scholar]
  87. 87.  Rengelshausen J, Göggelmann C, Burhenne J, Riedel K-D, Ludwig J et al. 2003. Contribution of increased oral bioavailability and reduced nonglomerular renal clearance of digoxin to the digoxin-clarithromycin interaction. Br. J. Clin. Pharmacol. 56:132–38
    [Google Scholar]
  88. 88.  Scotcher D, Jones CR, Galetin A, Rostami-Hodjegan A 2017. Delineating the role of various factors in renal disposition of digoxin through application of physiologically based kidney model to renal impairment populations. J. Pharmacol. Exp. Ther. 360:3484–95
    [Google Scholar]
  89. 89.  Kirby BJ, Collier AC, Kharasch ED, Whittington D, Thummel KE, Unadkat JD 2012. Complex drug interactions of the HIV protease inhibitors 3: effect of simultaneous or staggered dosing of digoxin and ritonavir, nelfinavir, rifampin, or bupropion. Drug Metab. Dispos. 40:3610–16
    [Google Scholar]
  90. 90.  Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmöller J et al. 2000. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. PNAS 97:73473–78
    [Google Scholar]
  91. 91.  Shoaf SE, Ohzone Y, Ninomiya S, Furukawa M, Bricmont P et al. 2011. In vitro P-glycoprotein interactions and steady-state pharmacokinetic interactions between tolvaptan and digoxin in healthy subjects. J. Clin. Pharmacol. 51:5761–69
    [Google Scholar]
  92. 92.  Vesell ES 1984. Noninvasive assessment in vivo of hepatic drug metabolism in health and disease. Ann. N. Y. Acad. Sci. 428:293–307
    [Google Scholar]
  93. 93.  Prueksaritanont T, Chu X, Evers R, Klopfer SO, Caro L et al. 2014. Pitavastatin is a more sensitive and selective organic anion-transporting polypeptide 1B clinical probe than rosuvastatin. Br. J. Clin. Pharmacol. 78:3587–98
    [Google Scholar]
  94. 94.  Graham GG, Punt J, Arora M, Day RO, Doogue MP et al. 2011. Clinical pharmacokinetics of metformin. Clin. Pharmacokinet. 50:281–98
    [Google Scholar]
  95. 95.  Elsby R, Chidlaw S, Outteridge S, Pickering S, Radcliffe A et al. 2017. Mechanistic in vitro studies confirm that inhibition of the renal apical efflux transporter multidrug and toxin extrusion (MATE) 1, and not altered absorption, underlies the increased metformin exposure observed in clinical interactions with cimetidine, trimethoprim or pyrimethamine. Pharmacol. Res. Perspect. 5:5e00357
    [Google Scholar]
  96. 96.  Ebner T, Ishiguro N, Taub ME 2015. The use of transporter probe drug cocktails for the assessment of transporter-based drug–drug interactions in a clinical setting—proposal of a four component transporter cocktail. J. Pharm. Sci. 104:93220–28
    [Google Scholar]
  97. 97.  Mathialagan S, Piotrowski MA, Tess DA, Feng B, Litchfield J, Varma MV 2017. Quantitative prediction of human renal clearance and drug-drug interactions of organic anion transporter substrates using in vitro transport data: a relative activity factor approach. Drug Metab. Dispos. 45:4409–17
    [Google Scholar]
  98. 98.  Dieterich A 2017. Mechanistische quantitative Bestimmung der Hemmung des Enzyms CYP3A in Leber und Darmwand mit einem neuartigen Studiendesign [Mechanistic quantitative assessment of the inhibition of the enzyme CYP3A in liver and gut wall using a novel study design] MD Thesis, Univ. Cologne Cologne, Ger:
  99. 99.  Hohmann N, Gottwald K, Czock D, Burhenne J, Haefeli WE, Mikus G 2016. Effects of the CYP3A perpetrators voriconazole, efavirenz and rifampin on midazolam plasma concentrations during continuous microdose infusion in healthy volunteers. Clin. Pharmacol. Ther. 99:Suppl. 1S40 (Abstr.)
    [Google Scholar]
  100. 100.  Croft M, Keely B, Morris I, Tann L, Lappin G 2012. Predicting drug candidate victims of drug-drug interactions, using microdosing. Clin. Pharmacokinet. 51:4237–46
    [Google Scholar]
  101. 101.  Nordmark A, Andersson A, Baranczewski P, Wanag E, Ståhle L 2014. Assessment of interaction potential of AZD2066 using in vitro metabolism tools, physiologically based pharmacokinetic modelling and in vivo cocktail data. Eur. J. Clin. Pharmacol. 70:2167–78
    [Google Scholar]
  102. 102.  Jetter A, Kinzig-Schippers M, Skott A, Lazar A, Tomalik-Scharte D et al. 2004. Cytochrome P450 2C9 phenotyping using low-dose tolbutamide. Eur. J. Clin. Pharmacol. 60:3165–71
    [Google Scholar]
  103. 103.  Nguyen TT, Bénech H, Delaforge M, Lenuzza N 2016. Design optimisation for pharmacokinetic modeling of a cocktail of phenotyping drugs. Pharm. Stat. 15:2165–77
    [Google Scholar]
  104. 104.  Prueksaritanont T, Tatosian D, Chu X, Railkar R, Evers R et al. 2017. Validation of a microdose probe drug cocktail for clinical drug interaction assessments for drug transporters and CYP3A. Clin. Pharmacol. Ther. 101:4519–30
    [Google Scholar]
  105. 105.  Chavez-Eng CM, Lutz RW, Goykhman D, Bateman KP 2018. Microdosing cocktail assay development for drug-drug interaction studies. J. Pharm. Sci. 107:71973–86
    [Google Scholar]
  106. 106.  Stehle S, Kirchheiner J, Lazar A, Fuhr U 2008. Pharmacogenetics of oral anticoagulants: a basis for dose individualization. Clin. Pharmacokinet. 47:9565–94
    [Google Scholar]
  107. 107.  de Andrés F, Terán S, Bovera M, Fariñas H, Terán E et al. 2016. Multiplex phenotyping for systems medicine: a one-point optimized practical sampling strategy for simultaneous estimation of CYP1A2, CYP2C9, CYP2C19, and CYP2D6 activities using a cocktail approach. OMICS 20:288–96
    [Google Scholar]
  108. 108.  Bosilkovska M, Samer C, Déglon J, Thomas A, Walder B et al. 2016. Evaluation of mutual drug-drug interaction within Geneva cocktail for cytochrome P450 phenotyping using innovative dried blood sampling method. Basic Clin. Pharmacol. Toxicol. 119:3284–90
    [Google Scholar]
  109. 109.  Masters JC, Harano DM, Greenberg HE, Tsunoda SM, Jang I-J, Ma JD 2015. Limited sampling strategy of partial area under the concentration-time curves to estimate midazolam systemic clearance for cytochrome P450 3A phenotyping. Ther. Drug Monit. 37:184–89
    [Google Scholar]
  110. 110.  Chang AT, Bertino JS, Nafziger AN, Kashuba ADM, Turpault S et al. 2016. S-Warfarin limited sampling models to estimate area under the concentration versus time curve for cytochrome P450 2C9 baseline activity and after induction. Ther. Drug Monit. 38:3383–87
    [Google Scholar]
  111. 111.  Varma MV, Pang KS, Isoherranen N, Zhao P 2015. Dealing with the complex drug-drug interactions: towards mechanistic models. Biopharm. Drug Dispos. 36:271–92
    [Google Scholar]
  112. 112.  Asaumi R, Toshimoto K, Tobe Y, Hashizume K, Nunoya K et al. 2018. Comprehensive PBPK model of rifampicin for quantitative prediction of complex drug-drug interactions: CYP3A/2C9 induction and OATP inhibition effects. CPT Pharmacomet. Syst. Pharmacol. 7:3186–96
    [Google Scholar]
  113. 113.  Rowland M, Peck C, Tucker G 2011. Physiologically-based pharmacokinetics in drug development and regulatory science. Annu. Rev. Pharmacol. Toxicol. 51:45–73Comprehensive description of the method and application of physiologically based pharmacokinetic models.
    [Google Scholar]
  114. 114.  Wendling T, Tsamandouras N, Dumitras S, Pigeolet E, Ogungbenro K, Aarons L 2016. Reduction of a whole-body physiologically based pharmacokinetic model to stabilise the bayesian analysis of clinical data. AAPS J 18:1196–209
    [Google Scholar]
  115. 115.  Tsamandouras N, Rostami-Hodjegan A, Aarons L 2015. Combining the “bottom up” and “top down” approaches in pharmacokinetic modelling: fitting PBPK models to observed clinical data. Br. J. Clin. Pharmacol. 79:148–55
    [Google Scholar]
  116. 116.  Wagner C, Pan Y, Hsu V, Sinha V, Zhao P 2016. Predicting the effect of CYP3A inducers on the pharmacokinetics of substrate drugs using physiologically based pharmacokinetic (PBPK) modeling: an analysis of PBPK submissions to the US FDA. Clin. Pharmacokinet. 55:4475–83
    [Google Scholar]
  117. 117.  Wagner C, Pan Y, Hsu V, Grillo JA, Zhang L et al. 2015. Predicting the effect of cytochrome P450 inhibitors on substrate drugs: analysis of physiologically based pharmacokinetic modeling submissions to the US Food and Drug Administration. Clin. Pharmacokinet. 54:1117–27
    [Google Scholar]
  118. 118.  Pelkonen O, Kapitulnik J, Gundert-Remy U, Boobis AR, Stockis A 2008. Local kinetics and dynamics of xenobiotics. Crit. Rev. Toxicol. 38:8697–720
    [Google Scholar]
  119. 119.  Korzekwa K, Nagar S 2017. On the nature of physiologically-based pharmacokinetic models—a priori or a posteriori? Mechanistic or empirical?. Pharm. Res. 34:3529–34
    [Google Scholar]
  120. 120.  de Andrés F, Llerena A 2016. Simultaneous determination of cytochrome P450 oxidation capacity in humans: a review on the phenotyping cocktail approach. Curr. Pharm. Biotechnol. 17:131159–80
    [Google Scholar]
  121. 121.  Donzelli M, Derungs A, Serratore MG, Noppen C, Nezic L et al. 2014. The Basel cocktail for simultaneous phenotyping of human cytochrome P450 isoforms in plasma, saliva and dried blood spots. Clin. Pharmacokinet. 53:3271–82
    [Google Scholar]
  122. 122.  Turpault S, Brian W, Van Horn R, Santoni A, Poitiers F et al. 2009. Pharmacokinetic assessment of a five-probe cocktail for CYPs 1A2, 2C9, 2C19, 2D6 and 3A. Br. J. Clin. Pharmacol. 68:6928–35Straightforward validation of a probe substrate cocktail.
    [Google Scholar]
  123. 123.  Stopfer P, Giessmann T, Hohl K, Sharma A, Ishiguro N et al. 2016. Pharmacokinetic evaluation of a drug transporter cocktail consisting of digoxin, furosemide, metformin, and rosuvastatin. Clin. Pharmacol. Ther. 100:3259–67A description of the first cocktail of transporter probe substrates.
    [Google Scholar]
  124. 124.  Stopfer P, Giessmann T, Hohl K, Sharma A, Ishiguro N et al. 2018. Effects of metformin and furosemide on rosuvastatin pharmacokinetics in healthy volunteers: implications for their use as probe drugs in a transporter cocktail. Eur. J. Drug Metab. Pharmacokinet. 43:169–80
    [Google Scholar]
  125. 125.  Stopfer P, Giessmann T, Hohl K, Hutzel S, Schmidt S et al. 2018. Optimization of a drug transporter probe cocktail: potential screening tool for transporter-mediated drug-drug interactions. Br. J. Clin. Pharmacol. 84:1941–49
    [Google Scholar]
  126. 126.  Pedersen RS, Damkier P, Christensen MM, Brosen K 2013. A cytochrome P450 phenotyping cocktail causing unexpected adverse reactions in female volunteers. Eur. J. Clin. Pharmacol. 69:121997–99
    [Google Scholar]
  127. 127.  Chow PKH, Yu W-K, Soo K-C, Chan STF 2003. The measurement of liver blood flow: a review of experimental and clinical methods. J. Surg. Res. 112:11–11
    [Google Scholar]
  128. 128.  van Griensven JM, Koster RW, Hopkins GR, Beier H, Günzler WA et al. 1997. Effect of changes in liver blood flow on the pharmacokinetics of saruplase in patients with acute myocardial infarction. Thromb. Haemost. 78:31015–20
    [Google Scholar]
  129. 129.  de Graaf W, Häusler S, Heger M, van Ginhoven TM, van Cappellen G et al. 2011. Transporters involved in the hepatic uptake of 99mTc-mebrofenin and indocyanine green. J. Hepatol. 54:4738–45
    [Google Scholar]
  130. 130.  Kagawa T, Adachi Y, Hashimoto N, Mitsui H, Ohashi T et al. 2017. Loss of organic anion transporting polypeptide 1B3 function causes marked delay in indocyanine green clearance without any clinical symptoms. Hepatology 65:31065–68
    [Google Scholar]
  131. 131.  Burns E, Triger DR, Tucker GT, Bax ND 1991. Indocyanine green elimination in patients with liver disease and in normal subjects. Clin. Sci. 80:2155–60
    [Google Scholar]
  132. 132.  Wissler EH 2011. Identifying a long standing error in single-bolus determination of the hepatic extraction ratio for indocyanine green. Eur. J. Appl. Physiol. 111:4641–46
    [Google Scholar]
  133. 133.  Keiding S, Engsted E, Ott P 1998. Sorbitol as a test substance for measurement of liver plasma flow in humans. Hepatology 28:150–56
    [Google Scholar]
  134. 134.  Seegmiller JC, Burns BE, Schinstock CA, Lieske JC, Larson TS 2016. Discordance between iothalamate and iohexol urinary clearances. Am. J. Kidney Dis. 67:149–55
    [Google Scholar]
  135. 135.  Schaeffner ES, Ebert N, Delanaye P, Frei U, Gaedeke J et al. 2012. Two novel equations to estimate kidney function in persons aged 70 years or older. Ann. Intern. Med. 157:7471–81
    [Google Scholar]
  136. 136.  Koteff J, Borland J, Chen S, Song I, Peppercorn A et al. 2013. A phase 1 study to evaluate the effect of dolutegravir on renal function via measurement of iohexol and para-aminohippurate clearance in healthy subjects. Br. J. Clin. Pharmacol. 75:4990–96
    [Google Scholar]
  137. 137.  Delanaye P, Melsom T, Ebert N, Bäck S-E, Mariat C et al. 2016. Iohexol plasma clearance for measuring glomerular filtration rate in clinical practice and research: a review. Part 2: Why to measure glomerular filtration rate with iohexol?. Clin. Kidney J. 9:5700–4
    [Google Scholar]
  138. 138.  Jetter A, Kinzig-Schippers M, Illauer M, Hermann R, Erb K et al. 2004. Phenotyping of N-acetyltransferase type 2 by caffeine from uncontrolled dietary exposure. Eur. J. Clin. Pharmacol. 60:117–21
    [Google Scholar]
  139. 139.  Polasek TM, Miners JO 2008. Macrolide-theophylline interactions: no role for the inhibition of cytochrome P4501A2. Br. J. Clin. Pharmacol. 66:6898–900
    [Google Scholar]
  140. 140.  Granfors M, Backman J, Neuvonen M, Neuvonen P 2004. Ciprofloxacin greatly increases concentrations and hypotensive effect of tizanidine by inhibiting its cytochrome P450 1A2-mediated presystemic metabolism. Clin. Pharmacol. Ther. 76:6598–606
    [Google Scholar]
  141. 141.  Momo K, Homma M, Osaka Y, Inomata S, Tanaka M, Kohda Y 2010. Effects of mexiletine, a CYP1A2 inhibitor, on tizanidine pharmacokinetics and pharmacodynamics. J. Clin. Pharmacol. 50:3331–37
    [Google Scholar]
  142. 142.  Bi Y, Mathialagan S, Tylaska L, Fu M, Keefer J et al. 2018. Organic anion transporter 2 mediates hepatic uptake of tolbutamide, a CYP2C9 probe drug. J. Pharmacol. Exp. Ther. 364:3390–98
    [Google Scholar]
  143. 143.  Yang M-S, Yu C-P, Chao P-DL, Lin S-P, Hou Y-C 2017. R- and S-warfarin were transported by breast cancer resistance protein: from in vitro to pharmacokinetic-pharmacodynamic studies. J. Pharm. Sci. 106:51419–25
    [Google Scholar]
  144. 144.  Bi Y, Lin J, Mathialagan S, Tylaska L, Callegari E et al. 2018. Role of hepatic organic anion transporter 2 in the pharmacokinetics of R- and S-warfarin: in vitro studies and mechanistic evaluation. Mol. Pharm. 15:31284–95
    [Google Scholar]
  145. 145.  Harris RZ, Salfi M, Posvar E, Hoelscher D, Padhi D 2007. Pharmacokinetics of desipramine HCl when administered with cinacalcet HCl. Eur. J. Clin. Pharmacol. 63:2159–63
    [Google Scholar]
  146. 146.  Brøsen K, Gram LF 1988. First-pass metabolism of imipramine and desipramine: impact of the sparteine oxidation phenotype. Clin. Pharmacol. Ther. 43:4400–6
    [Google Scholar]
  147. 147.  Samant T, Lukacova V, Schmidt S 2017. Development and qualification of physiologically based pharmacokinetic models for drugs with atypical distribution behavior: a desipramine case study. CPT Pharmacomet. Syst. Pharmacol. 6:5315–21
    [Google Scholar]
  148. 148.  Ciraulo DA, Barnhill JG, Jaffe JH 1988. Clinical pharmacokinetics of imipramine and desipramine in alcoholics and normal volunteers. Clin. Pharmacol. Ther. 43:5509–18
    [Google Scholar]
  149. 149.  Choi CI, Bae JW, Lee YJ, Lee HI, Jang CG, Lee SY 2014. Effects of CYP2C19 genetic polymorphisms on atomoxetine pharmacokinetics. J. Clin. Psychopharmacol. 34:1139–42
    [Google Scholar]
  150. 150.  Yu G, Li GF, Markowitz JS 2016. Atomoxetine: a review of its pharmacokinetics and pharmacogenomics relative to drug disposition. J. Child. Adolesc. Psychopharmacol. 26:4314–26
    [Google Scholar]
  151. 151.  Lucas D, Ferrara R, Gonzalez E, Bodenez P, Albores A et al. 1999. Chlorzoxazone, a selective probe for phenotyping CYP2E1 in humans. Pharmacogenetics 9:3377–88
    [Google Scholar]
  152. 152.  Palmer JL, Scott RJ, Gibson A, Dickins M, Pleasance S 2001. An interaction between the cytochrome P450 probe substrates chlorzoxazone (CYP2E1) and midazolam (CYP3A). Br. J. Clin. Pharmacol. 52:5555–61
    [Google Scholar]
  153. 153.  Blakey GE, Lockton JA, Perrett J, Norwood P, Russell M et al. 2004. Pharmacokinetic and pharmacodynamic assessment of a five-probe metabolic cocktail for CYPs 1A2, 3A4, 2C9, 2D6 and 2E1. Br. J. Clin. Pharmacol. 57:2162–69
    [Google Scholar]
  154. 154.  Masica A, Mayo G, Wilkinson G 2004. In vivo comparisons of constitutive cytochrome P450 3A activity assessed by alprazolam, triazolam, and midazolam. Clin. Pharmacol. Ther. 76:4341–49
    [Google Scholar]
  155. 155.  Kroboth PD, McAuley JW, Kroboth FJ, Bertz RJ, Smith RB 1995. Triazolam pharmacokinetics after intravenous, oral, and sublingual administration. J. Clin. Psychopharmacol. 15:4259–62
    [Google Scholar]
  156. 156.  Patki KC, Von Moltke LL, Greenblatt DJ 2003. In vitro metabolism of midazolam, triazolam, nifedipine, and testosterone by human liver microsomes and recombinant cytochromes P450: role of CYP3A4 and CYP3A5. Drug Metab. Dispos. 31:7938–44
    [Google Scholar]
  157. 157.  Zhao Y, Hu Z-Y 2014. Physiologically based pharmacokinetic modelling and in vivo [I]/Ki accurately predict P-glycoprotein-mediated drug-drug interactions with dabigatran etexilate. Br. J. Pharmacol. 171:41043–53
    [Google Scholar]
  158. 158.  Stangier J, Eriksson BI, Dahl OE, Ahnfelt L, Nehmiz G et al. 2005. Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement. J. Clin. Pharmacol. 45:5555–65
    [Google Scholar]
  159. 159.  Paré G, Eriksson N, Lehr T, Connolly S, Eikelboom J et al. 2013. Genetic determinants of dabigatran plasma levels and their relation to bleeding. Circulation 127:131404–12
    [Google Scholar]
  160. 160.  Maeda K, Tian Y, Fujita T, Ikeda Y, Kumagai Y et al. 2014. Inhibitory effects of p-aminohippurate and probenecid on the renal clearance of adefovir and benzylpenicillin as probe drugs for organic anion transporter (OAT) 1 and OAT3 in humans. Eur. J. Pharm. Sci. 59:94–103
    [Google Scholar]
  161. 161.  Stoffel M, Hsin C, Kinzig M, Schäffeler E, Lenssen R et al. 2017. Plasma pharmacokinetics in healthy volunteers does not suggest major changes in OATP1B1, OCT1/2, MATE1/2K, or OAT1/3 activities by a transporter phenotyping cocktail Presented at 14th European ISSX Meeting
  162. 162.  Chu X-Y, Bleasby K, Yabut J, Cai X, Chan GH et al. 2007. Transport of the dipeptidyl peptidase-4 inhibitor sitagliptin by human organic anion transporter 3, organic anion transporting polypeptide 4C1, and multidrug resistance P-glycoprotein. J. Pharmacol. Exp. Ther. 321:2673–83
    [Google Scholar]
  163. 163.  Klatt S, Fromm MF, König J 2011. Transporter-mediated drug-drug interactions with oral antidiabetic drugs. Pharmaceutics 3:4680–705
    [Google Scholar]
  164. 164.  Fujita K, Sakata H, Murono K, Hasegawa H, Takimoto M, Yoshioka H 1983. Comparative pharmacological evaluation of oral benzathine penicillin G and phenoxymethyl penicillin potassium in children. Pediatr. Pharmacol. 3:137–41
    [Google Scholar]
/content/journals/10.1146/annurev-pharmtox-010818-021909
Loading
/content/journals/10.1146/annurev-pharmtox-010818-021909
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error