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Diagnosing Biopharmaceutical Limitations

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Discovering and Developing Molecules with Optimal Drug-Like Properties

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 15))

Abstract

Obtaining optimal oral exposure in the drug discovery process can be a challenging goal for the discovery team, especially when the target therapy demands adequate exposure throughout the dosing interval and none of the compounds tested approaches the targeted exposure. Studying compounds to determine why exposure is poor may assist the structure–activity relationship (SAR) process, even if the compounds are not suitable for further development. Several in vitro, in vivo, and in silico tools are available to determine the cause for low exposure, so efforts can be focused on the chemistry needed to improve exposure. This chapter discusses various mechanisms that modulate absorption and exposure, as well as examines the tools that are available to determine the cause of poor exposure. The focus is on a balanced approach, of looking at (1) absorption, distribution, metabolism and excretion (ADME) (i.e., pharmacokinetic) considerations and (2) pharmaceutical properties to understand the underlying causes of poor exposure and approaches to address the problem efficiently.

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References

  • Akhtar N, Ahad A, Khar RK, Jaggi M, Aqil M, Iqbal Z, Ahmad FJ, Talegaonkar S (2011) The emerging role of P-glycoprotein inhibitors in drug delivery: a patent review. Expert Opin Ther Pat 21(4):561–576

    PubMed  CAS  Google Scholar 

  • Ali A (2012) A novel intranasal drug delivery system: review. Novel Sci Int Pharm Sci 1(8):550

    CAS  Google Scholar 

  • Allen JD, van Loevezijn A, Lakhai JM, van der Valk M, van Tellingen O, Reid G, Schellens JH, Koomen GJ, Schinkel AH (2002) Potent and specific inhibition of the breast cancer resistance protein multidrug transporter in vitro and in mouse intestine by a novel analogue of fumitremorgin C. Mol Cancer Ther 1(6):417–425

    PubMed  CAS  Google Scholar 

  • Amidon GL, Lennernas H, Shah VP, Crison JR (1995) A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res 12(3):413–420

    PubMed  CAS  Google Scholar 

  • Austin RP, Barton P, Cockroft SL, Wenlock MC, Riley RJ (2002) The influence of nonspecific microsomal binding on apparent intrinsic clearance, and its prediction from physicochemical properties. Drug Metab Dispos 30(12):1497–1503

    PubMed  CAS  Google Scholar 

  • Avdeef A (2001) Physicochemical profiling (solubility, permeability and charge state). Curr Top Med Chem 1(4):277–351

    PubMed  CAS  Google Scholar 

  • Balani SK, Zhu T, Yang TJ, Liu Z, He B, Lee FW (2002) Effective dosing regimen of 1-aminobenzotriazole for inhibition of antipyrine clearance in rats, dogs, and monkeys. Drug Metab Dispos 30(10):1059–1062

    PubMed  CAS  Google Scholar 

  • Baldwin SJ (1995) Ketoconazole and sulphaphenazole as the respective selective inhibitors of P4503A and 2C9. Xenobiotica 25(3):261–270

    PubMed  CAS  Google Scholar 

  • Balimane PV (2012) Permeability and transporter models in drug discovery and development. Wiley, Hoboken, NJ, pp 161–168

    Google Scholar 

  • Ballard P, Brassil P, Bui KH, Dolgos H, Petersson C, Tunek A, Webborn PJ (2012) The right compound in the right assay at the right time: an integrated discovery DMPK strategy. Drug Metab Rev 44(3):224–252

    PubMed  CAS  Google Scholar 

  • Beaumont K, Harper A, Smith DA, Bennett J (2000) The role of P-glycoprotein in determining the oral absorption and clearance of the NK2 antagonist, UK-224,671. Eur J Pharm Sci 12(1):41–50

    PubMed  CAS  Google Scholar 

  • Bell LC, Wang J (2012) Probe ADME and test hypotheses: a PATH beyond clearance in vitro-in vivo correlations in early drug discovery. Expert Opin Drug Metab Toxicol 8(9):1131–1155

    PubMed  CAS  Google Scholar 

  • Benet LZ (2010) Predicting drug disposition via application of a biopharmaceutics drug disposition classification system. Basic Clin Pharmacol Toxicol 106(3):162–167

    PubMed  CAS  PubMed Central  Google Scholar 

  • Benet LZ (2013) The role of BCS (biopharmaceutics classification system) and BDDCS (biopharmaceutics drug disposition classification system) in drug development. J Pharm Sci 102(1):34–42

    PubMed  CAS  PubMed Central  Google Scholar 

  • Bhattachar SN, Perkins EJ, Tan JS, Burns LJ (2011) Effect of gastric pH on the pharmacokinetics of a BCS class II compound in dogs: utilization of an artificial stomach and duodenum dissolution model and GastroPlus, simulations to predict absorption. J Pharm Sci 100(11):4756–4765

    PubMed  CAS  Google Scholar 

  • Bohnert T (2009) The role of drug metabolism in drug discovery. Wiley, Hoboken, NJ, pp 91–176

    Google Scholar 

  • Bollard M (2000) Pharmacokinetics and disposition of the novel dopamine agonist Z-7760 in rat after intravenous and oral administration. Xenobiotica 30(10):983–991

    PubMed  CAS  Google Scholar 

  • Boni JE, Brickl RS, Dressman J, Pfefferle ML (2009) Instant FaSSIF and FeSSIF—biorelevance meets practicality. Dissolution Technol 16(3):41–45

    CAS  Google Scholar 

  • Bosch I, Croop JM (1998) P-glycoprotein structure and evolutionary homologies. Cytotechnology 27(1–3):1–30

    PubMed  CAS  PubMed Central  Google Scholar 

  • Box KJ, Volgyi G, Baka E, Stuart M, Takacs-Novak K, Comer JE (2006) Equilibrium versus kinetic measurements of aqueous solubility, and the ability of compounds to supersaturate in solution–a validation study. J Pharm Sci 95(6):1298–1307

    PubMed  CAS  Google Scholar 

  • Camenisch G, Umehara K (2012) Predicting human hepatic clearance from in vitro drug metabolism and transport data: a scientific and pharmaceutical perspective for assessing drug-drug interactions. Biopharm Drug Dispos 33(4):179–194

    PubMed  CAS  Google Scholar 

  • Chen C, Liu X, Smith BJ (2003) Utility of Mdr1-gene deficient mice in assessing the impact of P-glycoprotein on pharmacokinetics and pharmacodynamics in drug discovery and development. Curr Drug Metab 4(4):272–291

    PubMed  CAS  Google Scholar 

  • Curatolo W (1998) Physical chemical properties of drug candidates in the discovery and exploratory development settings. PSTT 1(9):387–393

    CAS  Google Scholar 

  • Dai W-G, Dong LC, Song Y (2013) Enhanced bioavailability of poorly absorbed hydrophilic compounds through drug complex/in situ gelling formulation. Int J Pharm 457(1):63–70

    PubMed  CAS  Google Scholar 

  • Dai WG, Dong LC, Shi X, Nguyen J, Evans J, Xu Y, Creasey AA (2007) Evaluation of drug precipitation of solubility-enhancing liquid formulations using milligram quantities of a new molecular entity (NME). J Pharm Sci 96(11):2957–2969

    PubMed  CAS  Google Scholar 

  • Darby RA, Callaghan R, McMahon RM (2011) P-glycoprotein inhibition: the past, the present and the future. Curr Drug Metab 12(8):722–731

    PubMed  CAS  Google Scholar 

  • Dong JQ (2008) Applications of computer-aided pharmacokinetic and pharmacodynamic methods from drug discovery through registration. Curr Comput-Aided Drug Design 4(1):54

    CAS  Google Scholar 

  • Dressman JB, Vertzoni M, Goumas K, Reppas C (2007) Estimating drug solubility in the gastrointestinal tract. Adv Drug Deliv Rev 59(7):591–602

    PubMed  CAS  Google Scholar 

  • Emoto C, Murayama N, Rostami-Hodjegan A, Yamazaki H (2010) Methodologies for investigating drug metabolism at the early drug discovery stage: prediction of hepatic drug clearance and P450 contribution. Curr Drug Metab 11(8):678–685

    PubMed  CAS  Google Scholar 

  • FDA (2010) Guidance for industry M3(R2) nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals

    Google Scholar 

  • Feng B, Hurst S, Lu Y, Varma MV, Rotter CJ, El-Kattan A, Lockwood P, Corrigan B (2013) Quantitative prediction of renal transporter-mediated clinical drug-drug interactions. Mol Pharm 10(11):4207–4215

    PubMed  CAS  Google Scholar 

  • Friesen DT, Shanker R, Crew M, Smithey DT, Curatolo WJ, Nightingale JA (2008) Hydroxypropyl methylcellulose acetate succinate-based spray-dried dispersions: an overview. Mol Pharm 5(6):1003–1019

    PubMed  CAS  Google Scholar 

  • Galetin A, Gertz M, Houston JB (2010) Contribution of intestinal cytochrome p450-mediated metabolism to drug-drug inhibition and induction interactions. Drug Metab Pharmacokinet 25(1):28–47

    PubMed  CAS  Google Scholar 

  • Gao P, Shi Y (2012) Characterization of supersaturable formulations for improved absorption of poorly soluble drugs. AAPS J 14(4):703–713

    PubMed  CAS  PubMed Central  Google Scholar 

  • Garg S (2011) Buccal adhesive drug delivery system: safer delivery of biotherapeutics. J Drug Delivery Therapeutics 1(2):35

    CAS  Google Scholar 

  • Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X, Dahlin A, Evers R, Fischer V, Hillgren KM, Hoffmaster KA, Ishikawa T, Keppler D, Kim RB, Lee CA, Niemi M, Polli JW, Sugiyama Y, Swaan PW, Ware JA, Wright SH, Yee SW, Zamek-Gliszczynski MJ, Zhang L (2010) Membrane transporters in drug development. Nat Rev Drug Discov 9(3):215–236

    PubMed  CAS  Google Scholar 

  • Gleeson MP, Hersey A, Montanari D, Overington J (2011) Probing the links between in vitro potency, ADMET and physicochemical parameters. Nat Rev Drug Discov 10(3):197–208

    PubMed  CAS  Google Scholar 

  • Guo J (2011) In vitro and in vivo metabolism of a selective -opioid receptor. Drug Metab Dispos 39(10):1883–1894

    PubMed  CAS  Google Scholar 

  • Guo Y, Luo J, Tan S, Otieno BO, Zhang Z (2013) The applications of vitamin E TPGS in drug delivery. Eur J Pharm Sci 49(2):175–186

    PubMed  CAS  Google Scholar 

  • Heikkinen AT, Baneyx G, Caruso A, Parrott N (2012) Application of PBPK modeling to predict human intestinal metabolism of CYP3A substrates—an evaluation and case study using GastroPlus. Eur J Pharm Sci 47(2):375–386

    PubMed  CAS  Google Scholar 

  • Hirano M, Maeda K, Matsushima S, Nozaki Y, Kusuhara H, Sugiyama Y (2005) Involvement of BCRP (ABCG2) in the biliary excretion of pitavastatin. Mol Pharmacol 68(3):800–807

    PubMed  CAS  Google Scholar 

  • Hughes RD, Millburn P, Williams RT (1973) Molecular weight as a factor in the excretion of monoquaternary ammonium cations in the bile of the rat, rabbit and guinea pig. Biochem J 136(4):967–978

    PubMed  CAS  PubMed Central  Google Scholar 

  • Hyun-Jong C (2013) In vitro-in vivo extrapolation (IVIVE) for predicting human intestinal absorption and first-pass elimination of drugs: principles and applications. Drug Dev Ind Pharm

    Google Scholar 

  • Imaoka T (2013) Integrated approach of in vivo and in vitro evaluation of the involvement of hepatic uptake organic anion transporters in the drug disposition in rats using rifampicin as an inhibitor. Drug Metab Dispos 41(7):1442–1449

    PubMed  CAS  Google Scholar 

  • Iwatsubo T, Hirota N, Ooie T, Suzuki H, Shimada N, Chiba K, Ishizaki T, Green CE, Tyson CA, Sugiyama Y (1997) Prediction of in vivo drug metabolism in the human liver from in vitro metabolism data. Pharmacol Ther 73(2):147–171

    PubMed  CAS  Google Scholar 

  • Kalliokoski A, Niemi M (2009) Impact of OATP transporters on pharmacokinetics. Br J Pharmacol 158(3):693–705

    PubMed  CAS  PubMed Central  Google Scholar 

  • Kararli TT (1995) Comparison of the gastrointestinal anatomy, physiology, and biochemistry of humans and commonly used laboratory animals. Biopharm Drug Dispos 16(5):351–380

    PubMed  CAS  Google Scholar 

  • Keldenich J (2009) Measurement and prediction of oral absorption. Chem Biodivers 6(11):2000–2013

    PubMed  CAS  Google Scholar 

  • Khojasteh SC, Prabhu S, Kenny JR, Halladay JS, Lu AY (2011) Chemical inhibitors of cytochrome P450 isoforms in human liver microsomes: a re-evaluation of P450 isoform selectivity. Eur J Drug Metab Pharmacokinet 36(1):1–16

    PubMed  CAS  Google Scholar 

  • Lan LB, Dalton JT, Schuetz EG (2000) Mdr1 limits CYP3A metabolism in vivo. Mol Pharmacol 58(4):863–869

    PubMed  CAS  Google Scholar 

  • Landskroner KA, Hess P, Treiber A (2011) Surgical and pharmacological animal models used in drug metabolism and pharmacokinetics. Xenobiotica 41(8):687–700

    PubMed  CAS  Google Scholar 

  • Lau YY, Krishna G, Yumibe NP, Grotz DE, Sapidou E, Norton L, Chu I, Chen C, Soares AD, Lin CC (2002) The use of in vitro metabolic stability for rapid selection of compounds in early discovery based on their expected hepatic extraction ratios. Pharm Res 19(11):1606–1610

    PubMed  CAS  Google Scholar 

  • Lee YH, Perry BA, Lee HS, Kunta JR, Sutyak JP, Sinko PJ (2001) Differentiation of gut and hepatic first-pass effect of drugs: 1. Studies of verapamil in ported dogs. Pharm Res 18(12):1721–1728

    PubMed  CAS  Google Scholar 

  • Lentz KA (2008) Current methods for predicting human food effect. AAPS J 10(2):282–288

    PubMed  CAS  PubMed Central  Google Scholar 

  • Lentz KA, Quitko M, Morgan DG, Grace JE Jr, Gleason C, Marathe PH (2007) Development and validation of a preclinical food effect model. J Pharm Sci 96(2):459–472

    PubMed  CAS  Google Scholar 

  • Leucuta SE (2014) Selecting oral bioavailability enhancing formulations during drug discovery and development. Expert Opin Drug Discov 9(2):139–150

    PubMed  CAS  Google Scholar 

  • Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 46(1–3):3–26

    PubMed  CAS  Google Scholar 

  • Lubach JW, Chen JZ, Hau J, Imperio J, Coraggio M, Liu L, Wong H (2013) Investigation of the Rat model for preclinical evaluation of pH-dependent oral absorption in humans. Mol Pharm 10(11):3997–4004

    PubMed  CAS  Google Scholar 

  • Lui CY, Amidon GL, Berardi RR, Fleisher D, Youngberg C, Dressman JB (1986) Comparison of gastrointestinal pH in dogs and humans: implications on the use of the beagle dog as a model for oral absorption in humans. J Pharm Sci 75(3):271–274

    PubMed  CAS  Google Scholar 

  • Mahar KM, Portelli S, Coatney R, Chen EP (2012) Gastric pH and gastric residence time in fasted and fed conscious beagle dogs using the Bravo pH system. J Pharm Sci 101(7):2439–2448

    PubMed  CAS  Google Scholar 

  • Mathias NR, Crison J (2012) The use of modeling tools to drive efficient oral product design. AAPS J 14(3):591–600

    PubMed  CAS  PubMed Central  Google Scholar 

  • Meanwell NA (2011) Improving drug candidates by design: a focus on physicochemical properties as a means of improving compound disposition and safety. Chem Res Toxicol 24(9):1420–1456

    PubMed  CAS  Google Scholar 

  • Morrison J, Nophsker M (2009) Exploring and mapping “formulation space” for precipitation resistant vehicle development personal communication

    Google Scholar 

  • Murakami T, Nakanishi M, Yoshimori T, Okamura N, Norikura R, Mizojiri K (2003) Separate assessment of intestinal and hepatic first-pass effects using a rat model with double cannulation of the portal and jugular veins. Drug Metab Pharmacokinet 18(4):252–260

    PubMed  CAS  Google Scholar 

  • Nagilla R, Nord M, McAtee JJ, Jolivette LJ (2011) Cassette dosing for pharmacokinetic screening in drug discovery: comparison of clearance, volume of distribution, half-life, mean residence time, and oral bioavailability obtained by cassette and discrete dosing in rats. J Pharm Sci 100(9):3862–3874

    PubMed  CAS  Google Scholar 

  • Nishimura T, Kato Y, Amano N, Ono M, Kubo Y, Kimura Y, Fujita H, Tsuji A (2008) Species difference in intestinal absorption mechanism of etoposide and digoxin between cynomolgus monkey and rat. Pharm Res 25(11):2467–2476

    PubMed  CAS  Google Scholar 

  • Nomeir AA, Morrison R, Prelusky D, Korfmacher W, Broske L, Hesk D, McNamara P, Mei H (2009) Estimation of the extent of oral absorption in animals from oral and intravenous pharmacokinetic data in drug discovery. J Pharm Sci 98(11):4027–4038

    PubMed  CAS  Google Scholar 

  • Obach RS (1996) The importance of nonspecific binding in in vitro matrices, its impact on enzyme kinetic studies of drug metabolism reactions, and implications for in vitro-in vivo correlations. Drug Metab Dispos 24(10):1047–1049

    PubMed  CAS  Google Scholar 

  • Parker DD, Haskell RJ, Stefanski KJ (2013) Spray-dried dispersion performance. AAPS NERDG annual meeting, Rocky Hill, CT

    Google Scholar 

  • Perumal O (2013) Turning theory into practice: the development of modern transdermal drug delivery systems and future trends. Skin Pharmacol Physiol 26(4–6):331–342

    PubMed  CAS  Google Scholar 

  • Press B (2011) Optimization of the Caco-2 permeability assay to screen drug compounds for intestinal absorption and efflux. Methods Mol Biol 763:139–154

    PubMed  CAS  Google Scholar 

  • Reijenga J, van Hoof A, van Loon A, Teunissen B (2013) Development of methods for the determination of pKa values. Anal Chem Insights 8:53–71

    PubMed  CAS  PubMed Central  Google Scholar 

  • Rostami-Hodjegan A, Tucker GT (2007) Simulation and prediction of in vivo drug metabolism in human populations from in vitro data. Nat Rev Drug Discov 6(2):140–148

    PubMed  CAS  Google Scholar 

  • Saal C, Petereit AC (2012) Optimizing solubility: kinetic versus thermodynamic solubility temptations and risks. Eur J Pharm Sci 47(3):589–595

    PubMed  CAS  Google Scholar 

  • Sagawa K, Li F, Liese R, Sutton SC (2009) Fed and fasted gastric pH and gastric residence time in conscious beagle dogs. J Pharm Sci 98(7):2494–2500

    PubMed  CAS  Google Scholar 

  • Samiei N, Mangas-Sanjuan V, González-Álvarez I, Foroutan M, Shafaati A, Zarghi A, Bermejo M (2013) Ion-pair strategy for enabling amifostine oral absorption: Rat in situ and in vivo experiments. Eur J Pharm Sci 49(4):499–504

    PubMed  CAS  Google Scholar 

  • Schinkel AH, Mol CA, Wagenaar E, van Deemter L, Smit JJ, Borst P (1995) Multidrug resistance and the role of P-glycoprotein knockout mice. Eur J Cancer 31A(7–8):1295–1298

    PubMed  CAS  Google Scholar 

  • Schroeder HG, DeLuca PP (1974) A study on the in vitro precipitation of poorly soluble drugs from nonaqueous vehicles in human plasma. Bull Parenter Drug Assoc 28(1):1–14

    PubMed  CAS  Google Scholar 

  • Shen DD, Kunze KL, Thummel KE (1997) Enzyme-catalyzed processes of first-pass hepatic and intestinal drug extraction. Adv Drug Deliv Rev 27(2–3):99–127

    PubMed  Google Scholar 

  • Shitara Y (2011) Clinical importance of OATP1B1 and OATP1B3 in drug-drug interactions. Drug Metab Pharmacokinet 26(3):220–227

    PubMed  CAS  Google Scholar 

  • Sinha VK, Snoeys J, Osselaer NV, Peer AV, Mackie C, Heald D (2012) From preclinical to human—prediction of oral absorption and drug–drug interaction potential using physiologically based pharmacokinetic (PBPK) modeling approach in an industrial setting: a workflow by using case example. Biopharm Drug Dispos 33(2):111–121

    PubMed  CAS  Google Scholar 

  • Sinko PJ, Sutyak JP, Leesman GD, Hu P, Makhey VD, Yu H, Smith CL (1997) Oral absorption of anti-aids nucleoside analogues: 3. Regional absorption and in vivo permeability of 2′,3′-dideoxyinosine in an intestinal-vascular access port (IVAP) dog model. Biopharm Drug Dispos 18(8):697–710

    PubMed  CAS  Google Scholar 

  • Soars MG, Grime K, Sproston JL, Webborn PJ, Riley RJ (2007) Use of hepatocytes to assess the contribution of hepatic uptake to clearance in vivo. Drug Metab Dispos 35(6):859–865

    PubMed  CAS  Google Scholar 

  • Sohlenius-Sternbeck AK, Jones C, Ferguson D, Middleton BJ, Projean D, Floby E, Bylund J, Afzelius L (2012) Practical use of the regression offset approach for the prediction of in vivo intrinsic clearance from hepatocytes. Xenobiotica 42(9):841–853

    PubMed  CAS  Google Scholar 

  • Strelevitz TJ, Foti RS, Fisher MB (2006) In vivo use of the P450 inactivator 1-aminobenzotriazole in the rat: varied dosing route to elucidate gut and liver contributions to first-pass and systemic clearance. J Pharm Sci 95(6):1334–1341

    PubMed  CAS  Google Scholar 

  • Suzuyama N, Katoh M, Takeuchi T, Yoshitomi S, Higuchi T, Asashi S, Yokoi T (2007) Species differences of inhibitory effects on P-glycoprotein-mediated drug transport. J Pharm Sci 96(6):1609–1618

    PubMed  CAS  Google Scholar 

  • Takano R, Kataoka M, Yamashita S (2012) Integrating drug permeability with dissolution profile to develop IVIVC. Biopharm Drug Dispos 33(7):354–365

    PubMed  CAS  Google Scholar 

  • Takeda S (2006) Inhibition of UDP-glucuronosyltransferase 2b7-catalyzed morphine glucuronidation by ketoconazole: dual mechanisms involving a novel noncompetitive mode. Drug Metab Dispos 34(8):1277–1282

    PubMed  CAS  Google Scholar 

  • Thomas S, Brightman F, Gill H, Lee S, Pufong B (2008) Simulation modelling of human intestinal absorption using Caco-2 permeability and kinetic solubility data for early drug discovery. J Pharm Sci 97(10):4557–4574

    PubMed  CAS  Google Scholar 

  • Thummel KE (2002) The role of the gut mucosa in metabolically based drug-drug interaction. Drugs Pharm Sci 116(drug-drug interactions):359

    CAS  Google Scholar 

  • Tsume Y, Langguth P, Garcia-Arieta A, Amidon GL (2012) In silico prediction of drug dissolution and absorption with variation in intestinal pH for BCS class II weak acid drugs: ibuprofen and ketoprofen. Biopharm Drug Dispos 33(7):366–377

    PubMed  CAS  PubMed Central  Google Scholar 

  • van de Waterbeemd H, Smith DA, Jones BC (2001) Lipophilicity in PK design: methyl, ethyl, futile. J Comput Aided Mol Des 15(3):273–286

    PubMed  Google Scholar 

  • Ward KW, Stelman GJ, Morgan JA, Zeigler KS, Azzarano LM, Kehler JR, McSurdy-Freed JE, Proksch JW, Smith BR (2004) Development of an in vivo preclinical screen model to estimate absorption and first-pass hepatic extraction of xenobiotics. II. Use of ketoconazole to identify P-glycoprotein/CYP3A-limited bioavailability in the monkey. Drug Metab Dispos 32(2):172–177

    PubMed  CAS  Google Scholar 

  • Watanabe T, Kusuhara H, Maeda K, Kanamaru H, Saito Y, Hu Z, Sugiyama Y (2010) Investigation of the rate-determining process in the hepatic elimination of HMG-CoA reductase inhibitors in rats and humans. Drug Metab Dispos 38(2):215–222

    PubMed  CAS  Google Scholar 

  • Waterhouse RN (2003) Determination of lipophilicity and its use as a predictor of blood-brain barrier penetration of molecular imaging agents. Mol Imaging Biol 5(6):376–389

    PubMed  Google Scholar 

  • White RE (2011) Review of drug metabolism. Drug Discov Dev 1:3

    Google Scholar 

  • Wickremsinhe E, Bao J, Smith R, Burton R, Dow S, Perkins E (2013) Preclinical absorption, distribution, metabolism, and excretion of an oral amide prodrug of gemcitabine designed to deliver prolonged systemic exposure. Pharmaceutics 5(2):261–276

    PubMed  CAS  PubMed Central  Google Scholar 

  • Wu CY, Benet LZ (2005) Predicting drug disposition via application of BCS: transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm Res 22(1):11–23

    PubMed  CAS  Google Scholar 

  • Xia CQ, Xiao G, Liu N, Pimprale S, Fox L, Patten CJ, Crespi CL, Miwa G, Gan LS (2006) Comparison of species differences of P-glycoproteins in beagle dog, rhesus monkey, and human using Atpase activity assays. Mol Pharm 3(1):78–86

    PubMed  CAS  Google Scholar 

  • Yalkowsky S (1999) Solubility in aqueous media. Oxford University Press, New York

    Google Scholar 

  • Yengi LG, Leung L, Kao J (2007) The evolving role of drug metabolism in drug discovery and development. Pharm Res 24(5):842–858

    PubMed  CAS  Google Scholar 

  • Yoon IS, Choi MK, Kim JS, Shim CK, Chung SJ, Kim DD (2011) Pharmacokinetics and first-pass elimination of metoprolol in rats: contribution of intestinal first-pass extraction to low bioavailability of metoprolol. Xenobiotica 41(3):243–251

    PubMed  CAS  Google Scholar 

  • Yu L (2001) Amorphous pharmaceutical solids: preparation, characterization and stabilization. Adv Drug Deliv Rev 48(1):27–42

    PubMed  CAS  Google Scholar 

  • Yu LX, Straughn AB, Faustino PJ, Yang Y, Parekh A, Ciavarella AB, Asafu-Adjaye E, Mehta MU, Conner DP, Lesko LJ, Hussain AS (2004) The effect of food on the relative bioavailability of rapidly dissolving immediate-release solid oral products containing highly soluble drugs. Mol Pharm 1(5):357–362

    PubMed  CAS  Google Scholar 

  • Zara GP, Bargoni A, Cavalli R, Fundaro A, Vighetto D, Gasco MR (2002) Pharmacokinetics and tissue distribution of idarubicin-loaded solid lipid nanoparticles after duodenal administration to rats. J Pharm Sci 91(5):1324–1333

    PubMed  CAS  Google Scholar 

  • Zhang Y (1998) Effects of ketoconazole on the intestinal metabolism, transport and oral bioavailability of K02, a novel vinylsulfone peptidomimetic cysteine protease inhibitor and a P450 3A, P-glycoprotein dual substrate, in male Sprague-Dawley rats. J Pharmacol Exp Ther 287(1):246

    PubMed  CAS  Google Scholar 

  • Zhou R, Moench P, Heran C, Lu X, Mathias N, Faria TN, Wall DA, Hussain MA, Smith RL, Sun D (2005) pH-dependent dissolution in vitro and absorption in vivo of weakly basic drugs: development of a canine model. Pharm Res 22(2):188–192

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Metabolism and Pharmacokinetics, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT, 06492, USA

    Susan M. Jenkins

  2. Discovery Pharmaceutics, Bristol-Myers Squibb, Wallingford, CT, USA

    Dawn D. Parker

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  1. Susan M. Jenkins
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Correspondence to Susan M. Jenkins .

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Editors and Affiliations

  1. Pharmaceutical Sciences & Clinical Supply, Merck & Co, Inc., West Point, Pennsylvania, USA

    Allen C Templeton

  2. Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana, USA

    Stephen R. Byrn

  3. Discovery Pharmaceutics, Bristol-Myers Squibb, Wallingford, Connecticut, USA

    Roy J Haskell

  4. Department of Medicinal Chemistry, University of Kansas School of Pharmacy, Lawrence, Kansas, USA

    Thomas E. Prisinzano

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Jenkins, S.M., Parker, D.D. (2015). Diagnosing Biopharmaceutical Limitations. In: Templeton, A., Byrn, S., Haskell, R., Prisinzano, T. (eds) Discovering and Developing Molecules with Optimal Drug-Like Properties. AAPS Advances in the Pharmaceutical Sciences Series, vol 15. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1399-2_4

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