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WILEY SERIES ON PHARMACEUTICAL SCIENCE AND BIOTECHNOLOGY: PRACTICES, APPLICATIONS, AND METHODS

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CHAPTER 1: DRUG PHARMACOKINETICS AND TOXICOKINETICS

1.1 INTRODUCTION
1.2 TOXICITY ASSESSMENT IN DRUG DISCOVERY AND DEVELOPMENT
1.3 PARAMETERS THAT DEFINE PHARMACOKINETIC PROFILE
1.4 TOXICOGENOMICS AND BIOMARKERS
1.5 SPECIES DIFFERENCE IN DRUG DISPOSITION
1.6 MIST (METABOLITES IN SAFETY TESTING)
1.7 PHARMACOLOGICALLY ACTIVE METABOLITES
1.8 REACTIVE METABOLITES
1.9 ENABLING TECHNOLOGIES
1.10 CONCLUSION
1.11 CHAPTER 1 TUTORIAL
1.12 CHAPTER 1 TUTORIAL ANSWERS KEY
REFERENCES

CHAPTER 2: GIT ANATOMY AND PHYSIOLOGY AND DRUG ORAL BIOAVAILABILITY: IMPACT OF SPECIES DIFFERENCES

2.1 INTRODUCTION
2.2 PHYSIOLOGICAL FACTORS THAT IMPACT ORAL DRUG ABSORPTION
2.3 MECHANISM OF ORAL ABSORPTION
2.4 PHYSIOLOGICAL FACTORS THAT IMPACT DRUG METABOLISM
2.5 CONCLUSION
2.6 CHAPTER 2 TUTORIALS
2.7 CHAPTER 2 TUTORIALS KEY
REFERENCES

CHAPTER 3: DRUG ROUTES OF EXCRETION

3.1 INTRODUCTION
3.2 RENAL ELIMINATION
3.3 HEPATOBILIARY ELIMINATION
3.4 CONCLUSION
3.5 CHAPTER 3 TUTORIALS
3.6 CHAPTER 3 TUTORIAL ANSWERS KEY
REFERENCES

CHAPTER 4: PHYSICOCHEMICAL AND BIOPHARMACEUTICAL PROPERTIES THAT AFFECT DRUG ABSORPTION OF COMPOUNDS ABSORBED BY PASSIVE DIFFUSION

4.1 INTRODUCTION
4.2 MECHANISM OF ORAL ABSORPTION VIA PASSIVE DIFFUSION
4.3 PHYSICOCHEMICAL AND BIOPHARMACEUTICAL PROPERTIES THAT INFLUENCE PASSIVE PERMEABILITY
4.4 SOLUBILITY
4.5 PHYSICOCHEMICAL AND BIOPHARMACEUTICAL PROPERTIES THAT INFLUENCE SOLUBILITY
4.6 APPROACHES TO INCREASE DRUG DISSOLUTION
4.7 PHYSICOCHEMICAL AND BIOPHARMACEUTICAL PROPERTIES THAT INFLUENCE DISSOLUTION
4.8 THE USE OF PRODRUGS TO INCREASE SOLUBILITY AND PERMEABILITY
4.9 BIOPHARMACEUTICS CLASSIFICATION SYSTEM (BCS) AND DRUG
4.10 CONCLUSION
4.11 CHAPTER 4 TUTORIALS
4.12 CHAPTER 4 TUTORIALS ANSWERS KEY
REFERENCES

CHAPTER 5: PHYSICOCHEMICAL AND BIOPHARMACEUTICAL FACTORS AFFECTING HEPATIC/INTESTINAL FIRST-PASS EFFECT

5.1 INTRODUCTION
5.2 PHYSICOCHEMICAL APPROACHES TO INCREASE METABOLIC STABILITY
5.3 CONCLUSION
5.4 TUTORIAL CHAPTER 5
5.5 TUTORIAL CHAPTER 5 ANSWER KEY
REFERENCES

CHAPTER 6: IMPACT OF INTESTINAL EFFLUX TRANSPORTERS ON ORAL ABSORPTION

6.1 INTRODUCTION
6.2 INTESTINAL EFFLUX TRANSPORTERS
6.3 CONCLUSION
6.4 CHAPTER 6 TUTORIALS
6.5 CHAPTER 6 TUTORIAL ANSWER KEY
REFERENCES

CHAPTER 7: IMPACT OF INFLUX TRANSPORTERS ON DRUG ABSORPTION

7.1 INTRODUCTION
7.2 INTESTINAL DRUG TRANSPORTERS
7.3 DRUG ABSORPTION AND CONCENTRATION GRADIENT
7.4 CONCLUSION
7.5 CHAPTER 7 TUTORIALS
7.6 CHAPTER 7 TUTORIALS ANSWERS KEY
REFERENCES

CHAPTER 8: EXTENDED CLEARANCE CLASSIFICATION SYSTEM (ECCS) AND ITS UTILITY IN PREDICTING CLEARANCE RATE-DETERMINING STEP IN DRUG DISCOVERY

8.1 INTRODUCTION
8.2 HEPATIC CLEARANCE
8.3 RENAL CLEARANCE
8.4 PROPOSAL OF EXTENDED CLEARANCE CLASSIFICATION SYSTEM (ECCS)
8.5 CONCLUSIONS
8.6 CHAPTER 8 TUTORIALS
8.7 CHAPTER 8 TUTORIAL ANSWER KEY
REFERENCES

CHAPTER 9: IN VITRO AND IN SITU APPROACHES TO MEASURE INTESTINAL PERMEABILITY AND EFFLUX TRANSPORTERS

9.1 INTRODUCTION
9.2 PARALLEL ARTIFICIAL MEMBRANE PERMEABILITY ASSAY
9.3 C-2 AND MDCK IMPLEMENTATION IN DRUG DISCOVERY AND DEVELOPMENT
9.4 SINGLE-PASS INTESTINAL PERFUSION
9.5 MISCELLANEOUS PERMEABILITY MODELS AND TECHNOLOGIES REVIEW
9.6 CONCLUSION
REFERENCES

CHAPTER 10: IN SILICO APPROACHES TO PREDICT INTESTINAL PERMEABILITY

10.1 INTRODUCTION
10.2 PREDICTION OF HUMAN INTESTINAL PERMEABILITY AND ABSORPTION BASED ON I PERMEABILITY INPUTS
10.3 CONCLUSION
REFERENCES

CHAPTER 11: IN VIVO PRECLINICAL APPROACHES TO DECONVOLUTE THE CONTRIBUTION OF FIRST-PASS EFFECT FROM ORAL ABSORPTION

11.1 INTRODUCTION
11.2 IN VIVO ESTIMATION OF ORAL BIOAVAILABILITY AND ITS COMPONENTS
11.3 FRACTION OF THE DOSE ABSORBED INTO THE PORTAL BLOOD AFTER ORAL ADMINISTRATION (F_A·F_G)
11.4 APPROACHES TO DIFFERENTIATE THE POOR ABSORPTION FROM FIRST-PASS EFFECT CONTRIBUTION TO LOW ORAL BIOAVAILABILITY
11.5 APPROACHES TO ASSESS THE PHARMACODYNAMICS ACTIVITY OF NME WITH POOR ORAL BIOAVAILABILITY
11.6 CONCLUSION
11.7 TUTORIAL CHAPTER 11
11.8 CHAPTER 11 TUTORIAL ANSWER KEY
REFERENCES

CHAPTER 12: IN VITRO APPROACHES TO ASSESS HEPATIC METABOLISM AND FIRST-PASS EFFECT

12.1 INTRODUCTION
12.2 IN VITRO TOOLS AVAILABLE TO MEASURE METABOLIC CLEARANCE
12.3 STEPS TO MEASURE IN VIVO HEPATIC CLEARANCE
12.4 CONCLUSION
12.5 CHAPTER 12 TUTORIALS
12.6 CHAPTER 12 TUTORIAL ANSWER KEY
REFERENCES

CHAPTER 13: THE UTILITY OF ECCS AS A ROADMAP TO IMPROVE ORAL BIOAVAILABILITY OF NEW MOLECULAR ENTITIES: INDUSTRIAL PERSPECTIVE

13.1 INTRODUCTION
13.2 ECCS CLASSIFICATION
13.3 f_a MODULATION
13.4 f_g
13.5 HEPATIC CLEARANCE
13.6 CONCLUSION
13.7 CHAPTER 13 TUTORIALS
13.8 CHAPTER 13 TUTORIAL ANSWERS KEY
REFERENCES

INDEX

END USER LICENSE AGREEMENT

list of Illustrations

CHAPTER 1: DRUG PHARMACOKINETICS AND TOXICOKINETICS

Figure 1.1 The contribution of various factors to the overall attrition of NCEs in year 2001.
Figure 1.2 The relationship between drug oral bioavailability and interindividual variability reported as coefficient of variation (%).
Figure 1.3 Estimation of the area under the plasma concentration–time curve (AUC).
Figure 1.4 Various routes/mechanisms of eliminations that contribute to drug CL_total.
Figure 1.5 Volume of distribution and its relation with the extent of drug distribution in blood and tissues.
Figure 1.6 Tissue and blood binding and their impact on drug volume of distribution.
Figure 1.7 Plasma concentration–time profiles for drugs with half-lives of 6, 36, or 99 h administered once daily. Simulations were performed using Berkeley Madonna Software^®. (a) Half-life is 6 h (e.g., atenolol); (b) half-life is 99 h (e.g., phenobarbital).
Figure 1.8 The semilog plot of plasma profile versus time of a compound that follows one compartment model with first-order input and first-order output.
Figure 1.9 The semilog plot of residual versus time.
Figure 1.10 The impact of changes in k_a values on the oral plasma profile of a compound.
Figure 1.11 Oral bioavailability is a multiplicity parameter and a product of f_a, f_g, and f_h.
Figure 1.12 The relationship between drug elimination/transport rate and free drug concentration for a Michaelis–Menten kinetics complying biological process.
Figure 1.13 The relationship between dose and AUC is indicator of presence or absence of drug linearity.
Figure 1.14 One-compartment model.
Figure 1.15 Two-compartment model.
Figure 1.16 Physiologically based pharmacokinetic (PBPK) model incorporating physiological compartments depending on the drug's distribution.
Figure 1.17 Known drug and system parameters used to build PBPK models.
Figure 1.18 Perfusion- and permeability-limited distribution.

CHAPTER 2: GIT ANATOMY AND PHYSIOLOGY AND DRUG ORAL BIOAVAILABILITY: IMPACT OF SPECIES DIFFERENCES

Figure 2.1 Plot of oral bioavailability (F) in animal species versus oral bioavailability in humans (in percentage). Diamonds are for mouse, circles for rats, triangles for dogs, and squares for nonhuman primates (NHP).
Figure 2.2 Comparative bulk pH across the gastrointestinal tract of rats, dogs, monkeys, and humans [25, 30].
Figure 2.3 The chemical structures of taurocholic acid and deoxycholic acid, respectively.
Figure 2.4 Possible routes of drug absorption across intestinal enterocytes.
Figure 2.5 Correlations of P-gp binding affinity (αKa) between human MDR1 and rhesus monkey Mdr1 (a) and between human MDR1 and beagle dog Mdr1 (b).
Figure 2.6 Uptake of [³H]estradiol-17β-d-glucuronide (1 μM), [³H]cholecystokinin octapeptide (0.1 μM) and [³H]estrone-3-sulfate (1 μM) into mock, cynomolgus OATP2B1, and human OATP2B1 expressing HEK-293 cells was determined following 1.5 min of incubation.
Figure 2.7 Correlation of percent of oral dose absorbed (f_a) between humans versus rats (a), monkeys (b), and dogs (c).
Figure 2.8 Major UDP-glucuronosyltransferases expressed in human liver and intestine based on protein level using proteomic approaches.
Figure 2.9 Expression of UDP-glucuronosyltransferase mRNAs in cynomolgus monkey large intestine, liver, and small intestine.
Figure 2.10 Chemical structures of FK3453 and M4. Zwisler et al. 2010. [192]. Reproduced with permission of John Wiley & Sons.

CHAPTER 4: PHYSICOCHEMICAL AND BIOPHARMACEUTICAL PROPERTIES THAT AFFECT DRUG ABSORPTION OF COMPOUNDS ABSORBED BY PASSIVE DIFFUSION

Figure 4.1 The relationship between PSA and human f_a for a set of 309 molecules.
Figure 4.2 The relationship between lipophilicity descriptor parameters and human f_a using a set of 309 compounds (a) c log P and (b) c log D_7.4. Varma et al. 2010 [4] with permission.
Figure 4.3 Schematic diagram to illustrate the relationship between the fraction of drug unionized, and pH and pK_a of (a) bases and (b) acids.
Figure 4.4 The relationship between compound ionization state and human f_a (n = 309). Varma et al. 2010 [4] with permission.
Figure 4.5 Relationship between number of violations of RO5 and bioavailability and individual processes. “n” is the number of compounds in each bin [4] with permission.
Figure 4.6 The solubility ratio for polymorphs (n = 81).
Figure 4.7 N-alkylation of thalidomide alters the highly ordered crystal lattice and increases its solubility by fourfold.
Figure 4.8 Dissolution of a salt form of organic acid in gastric fluid.
Figure 4.9 The chemical structures of α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin.
Figure 4.10 The dissolution rate of ritonavir in 0.1 N HCl at 37 °C using crystalline (0.03 mg/cm²/min) and amorphous forms (0.3 mg/cm²/min). Law et al. 2004 [48] with permission.
Figure 4.11 The C_max (µg/mL) and AUC (µg*h/mL) of various ritonavir dispersions in beagle dogs.
Figure 4.12 Known functional groups on parent drugs that are pliable to prodrug design (shown in gray).
Figure 4.13 Bioconversion pathways of famciclovir to penciclovir.
Figure 4.14 The chemical structures of acyclovir and its commercial prodrug valacyclovir, respectively, with acyclovir bioavailability following oral dosing in humans for the two agents [80–82].
Figure 4.15 The chemical structures of gabapentin and its commercial prodrug XP13512 (Gabapentin enacarbil).

CHAPTER 5: PHYSICOCHEMICAL AND BIOPHARMACEUTICAL FACTORS AFFECTING HEPATIC/INTESTINAL FIRST-PASS EFFECT

Figure 5.1 CYP isoforms relative content in (a) human liver and (b) intestine, respectively [13, 14].
Figure 5.2 A decision tree for human CYP450 substrates based on compounds V_dss, ionization, and planarity.
Figure 5.3 The mechanism of glucuronide conjugate formation using UDP-glucuronyl transferase. Nu is a nucleophilic site on a drug molecule.
Figure 5.4 The relationship between MDCK-LE permeability and human f_a. Human f_a > 80% (horizontal dotted line) where a permeability value of 5 × 10⁻⁶ cm/s cutoff value would differentiate between low and high values.
Figure 5.5 The relationship between calculated lipophilicity (c log D) and drug fraction that escapes (a) intestinal and (b) hepatic first-pass effects, respectively.
Figure 5.6 The relationship between lipophilicity (log D) and affinity to CYP3A4 substrates corrected for microsomal protein binding for a set of CYP3A4 substrates [28–47].
Figure 5.7 The substitution of bifluorobenzyl group with ethyl group increased plasma exposure observed in monkeys at 7 h following 7 h oral dosing and maintained antiviral activity.
Figure 5.8 The relationship between the compound polar surface area (PSA) and the fraction that escapes hepatic first-pass effect (f_h).
Figure 5.9 Chemical structure of cholesterol absorption inhibitors including ezetimibe [56–58].
Figure 5.10 The rate of para position hydroxylation of phenobarbital was reduced by chlorination [7, 59].
Figure 5.11 The metabolic rate of O-dealkylation of metoprolol [8] was reduced by replacing the methoxy group with the bulky aliphatic cyclopropyl methoxy group to form betaxolol [9, 62].
Figure 5.12 Sensitivity analysis of the impacts of f_u,p and f_u,mic on human CL using SimCYP 13.1.
Figure 5.13 The relationship between in vivo rat clearance and human clearance.
Figure 5.14 The chemical structures of bambuterol and terbutaline.
Figure 5.15 The relationship between intrinsic in vitro intestinal clearance (CLu_int,g), effective intestinal permeability (P_eff), and f_g for the prediction of intestinal extraction from in vitro data using Q_gut model.

CHAPTER 6: IMPACT OF INTESTINAL EFFLUX TRANSPORTERS ON ORAL ABSORPTION

Figure 6.1 Intestinal protein expression of intestinal efflux transporters (ABCB1, ABCC2, and ABCG2) in human jejunum and ileum (N = 4).
Figure 6.2 Protein expression of efflux transporters in human jejunum (N = 4) and Caco-2 (N = 4). (*Below limit of quantification.).
Figure 6.3 Physicochemical properties of known P-gp substrates: (a) measured log D_{pH 7.4}, measured log P, HBD, and HBA of known P-gp substrates; (b) polar surface area (PSA), molecular weight (M_wt), efflux ratio, and reported K_m of known P-gp substrates [17–93].
Figure 6.4 The relationship between measured log P and K_m values of P-gp substrates. Data obtained from Table 6.1 [17–93].
Figure 6.5 The relationship between efflux ratio and K_m of P-gp substrates. Data obtained from Table 6.1.
Figure 6.6 The C_max and AUC of talinololfollowing single doses of 100-mg talinolol immediate-release, 100-mg talinolol controlled-release.
Figure 6.7 The median changes in the AUC between pharmacogenetic variant and wild-type carrier (ABCB1) volunteers based on BDDCS Classes [156, 159–193].
Figure 6.8 Physicochemical properties of known BCRP substrates: (a) measured log D_{pH 7.4}, measured log P, HBD, and HBA of known BCRP substrates; (b) polar surface area (PSA), molecular weight (M_wt), efflux ratio, and reported K_m of known BCRP substrates [18, 25, 35, 60, 87, 223–249].
Figure 6.9 The relationship between F_a * F_g and the talinolol dose in humans. The triangles represent actual observed F_a * F_g at various oral doses. The lines represent fitted or simulated results based on changes in input parameters. Sensitivity analysis was run for (a) K_m, (b) V_max, (c) P_eff, and (d) solubility.
Figure 6.10 A proposed decision tree for predicting nonlinear pharmacokinetics of P-gp/CYP3A4 substrates.

CHAPTER 7: IMPACT OF INFLUX TRANSPORTERS ON DRUG ABSORPTION

Figure 7.1 Known proton-coupled/pH-dependent solute carriers expressed at the brush border membrane of small intestine.
Figure 7.2 Intestinal protein expression of clinically relevant uptake (OATP2B1, PepT1) transporters in human jejunum and ileum from four donors quantified using validated mass spectrometry-based targeted proteomic.
Figure 7.3 Protein expression of clinically relevant intestinal influx transporters in human jejunum (N = 4) and in Caco-2 cells (N = 4). Mean ± SD are given.
Figure 7.4 Chemical structures of estrone-3-sulfate and statins.
Figure 7.5 pH-Dependent uptake of E-3-S and statins by the mock-transfected and OATP2B1-transfected cells. Uptake by mock-transfected () and OATP2B1-transfected (Δ) cells was measured over 2 min, at various extracellular pH values in the range of 5.5 and 7.4. OATP2B1-mediated uptake () was obtained by subtracting the uptake in the mock-transfected cells from that by the OATP2B1-transfected cells.
Figure 7.6 The impact of grapefruit juice on atorvastatin acid, losartan, lovastatin, and simvastatin plasma exposure AUC_Δ% in healthy volunteers [43–50].
Figure 7.7 The physicochemical properties of OATP2B1 substrates (a) M_wt and PSA, (b) cMDCK-LE and c log D.
Figure 7.8 Schematic representation of the single-nucleotide polymorphisms in structure of OATP2B1. Arrows indicate alteration of in vitro functional activity of the variant protein. ↓: Reduced activity, ↑: increased activity.
Figure 7.9 The AUC_(0→∞) and C_max parameters of fexofenadine following oral administration of 60 mg orally with water in relation to the SLCO2B1 c.1457C>T polymorphism.
Figure 7.10 The mean plasma concentration of cefadroxil in healthy volunteers in absence (-•-) and presence (-o-) of 5 mg/kg cephalexin (45 mg/kg).
Figure 7.11 Key features in compounds determining recognition as a peptide transporter substrate. The structural components that critically control affinity of key elements are presented on the backbone of a tripeptide as model compound.
Figure 7.12 Dose proportionality of gabapentin blood AUC_(0→∞) following single oral doses of XP13512 immediate release capsules or oral gabapentin.

CHAPTER 8: EXTENDED CLEARANCE CLASSIFICATION SYSTEM (ECCS) AND ITS UTILITY IN PREDICTING CLEARANCE RATE-DETERMINING STEP IN DRUG DISCOVERY

Figure 8.1 The framework of extended clearance classification system (ECCS) for identifying the predominant mechanism that determines systemic clearance of drugs [10].

CHAPTER 9: IN VITRO AND IN SITU APPROACHES TO MEASURE INTESTINAL PERMEABILITY AND EFFLUX TRANSPORTERS

Figure 9.1 Schematic diagram of a PAMPA donor/acceptor compartments assembly.
Figure 9.2 Systematic design of the in vitro cell culture monolayer experiment.
Figure 9.3 The relationship between rat P_eff versus human f_a [48, 49].

CHAPTER 11: IN VIVO PRECLINICAL APPROACHES TO DECONVOLUTE THE CONTRIBUTION OF FIRST-PASS EFFECT FROM ORAL ABSORPTION

Figure 11.1 The chemical structure of 1-aminobenzotriazole.
Figure 11.2 The impact of ABT route of administration with 1-h pretreatment on the oral plasma exposure (AUC) of midazolam (10 mg/kg) [9].
Figure 11.3 The chemical structure of CP-100,356 [10].
Figure 11.4 The chemical structure of elacridar (GF120198).
Figure 11.5 The relationship of the AUC ratio between monkeys (with elacridar (EL)/without elacridar (UT)) and human (ABCG2 421AA/CC) after oral administration of rosuvastatin (•), pitavastatin (◼), fluvastatin (○), and sulfasalazine (Δ). The solid lines represent a 1:1 correspondence and the dotted lines represent the twofold difference.
Figure 11.6 The impact of 1000 mg of GF-120198 PO dose on the renal recovery and exposure of Topotecan (1 mg/m² PO dose).
Figure 11.7 The impact of formulation on the renal recovery (Xu%) and AUC following acyclovir 2.5 mg/kg PO dose [13].
Figure 11.8 The chemical structures of zosuquidar and Ko143, respectively.
Figure 11.9 The f_a·f_g of fexofenadine (5 mg/kg), sulfasalazine (5 mg/kg), and topotecan (0.3 mg/kg) following ZSQ (30 mg/kg) and/or Ko143 (10 mg/kg) in portal vein cannulated rats.
Figure 11.10 The relationship between rat and human clearance.
Figure 11.11 Routes of administration to assess biological activity in preclinical species.
Figure 11.12 Plasma [S,S]-reboxetine concentration–time profiles after intravenous, subcutaneous, intraperitoneal, and oral administration (5 mg/kg) of [S,S]-reboxetine to Sprague Dawley rats (Pfizer internal data).

CHAPTER 13: THE UTILITY OF ECCS AS A ROADMAP TO IMPROVE ORAL BIOAVAILABILITY OF NEW MOLECULAR ENTITIES: INDUSTRIAL PERSPECTIVE

Figure 13.1 The relationship between LE-MDCK permeability versus human f_a for set of compounds classified based on ECCS.
Figure 13.2 The median and average of f_a for compounds classified based on their ECCS.
Figure 13.3 The median, average, and range of f_g for compounds classified based on their ECCS.
Figure 13.4 The median, average, and range of CL_h for compounds classified based on their ECCS.
Figure 13.5 The median, average, and range of f_h for compounds classified based on their ECCS.
Figure 13.6 The median, average, and range of f for compounds classified based on their ECCS.

List of Tables

CHAPTER 1: DRUG PHARMACOKINETICS AND TOXICOKINETICS

Table 1.1 Typical Body Weight and Hepatic Blood Flow for Various Preclinical Species and Human
Table 1.2 The Factors that may Contribute to Drug Nonlinear Kinetics
Table 1.3 Examples of Human Drug Metabolites that are known to be Responsible for General Toxicity and Potentially Idiosyncratic Drug Toxicity

CHAPTER 2: GIT ANATOMY AND PHYSIOLOGY AND DRUG ORAL BIOAVAILABILITY: IMPACT OF SPECIES DIFFERENCES

Table 2.1 Comparison of the Anatomical Lengths of the Intestinal Tract and Its Major Subdivision in Rats, Dogs, Monkeys, and Humans [9–12]
Table 2.2 Comparison of the Absolute Surface Areas and Surface Area of the Gastrointestinal Tract Relative to Total Body Surface Area in Rats, Dogs, Monkeys, and Humans [8–11]
Table 2.3 The Impact of Food Caloric Density and Meal Volume on the Gastric Emptying Rate in Humans
Table 2.4 The Absorption of a Set of Hydrophilic Drugs in Rats, Dogs, and Humans
Table 2.5 Relative Expression of mRNA for MDR1, MRP2, and BCRP in Small Intestine and Colon of Cynomolgus Monkeys and Humans Determined using RT-PCR
Table 2.6 The Absorption of a Set of PEPT1 Transporter Substrates in Rats, Dogs, Monkeys, and Humans [95–97]
Table 2.7 CYP Enzymes of Major Drug Metabolizing CYP Family in Human, Mouse, Rat, Dog, and Monkey

CHAPTER 3: DRUG ROUTES OF EXCRETION

Table 3.1 Partial List of Known OAT1 Transporter Substrates
Table 3.2 Partial List of Known OAT3 Transporter Substrates
Table 3.3 Partial List of Known OCT2 Transporter Substrates
Table 3.4 Partial List of Known Compounds that are Substrates for MATE1 Transporters
Table 3.5 Partial List of Known Compounds that are Substrates for MATE2K Transporters
Table 3.6 Partial List of Known Compounds that are Substrates for OATP1B1 Transporters
Table 3.7 Partial List of Known Compounds that are Substrates for OATP1B3 Transporters
Table 3.8 Partial List of Known Compounds that are Substrates for OCT1 Transporters
Table 3.9 Partial List of Known Compounds that are Substrates for MRP2 Transporters

CHAPTER 4: PHYSICOCHEMICAL AND BIOPHARMACEUTICAL PROPERTIES THAT AFFECT DRUG ABSORPTION OF COMPOUNDS ABSORBED BY PASSIVE DIFFUSION

Table 4.1 Marketed Cyclodextrin-Containing Drug Products

CHAPTER 5: PHYSICOCHEMICAL AND BIOPHARMACEUTICAL FACTORS AFFECTING HEPATIC/INTESTINAL FIRST-PASS EFFECT

Table 5.1 Classification of Hepatic Metabolic Stability Based on Human and Rat Liver Microsomes and Human Hepatocytes
Table 5.2 In Vitro t_1/2, Intrinsic Clearance, Microsomal and Plasma Fraction Unbound, Blood to Plasma Ratio, and Blood Clearance of a Set of Drugs
Table 5.3 The Oral Bioavailability of Nalbuphine Following Oral Dosing of the Parent Drug and Its Acetylsalicylate and Anthranilate Esters in Dogs
Table 5.4 List of Drug Candidates That Have Dropped in Clinical Trials due to Poor Oral Pharmacokinetic Profiles or Toxicity Ascribed to AO Metabolism

CHAPTER 6: IMPACT OF INTESTINAL EFFLUX TRANSPORTERS ON ORAL ABSORPTION

Table 6.1 Partial List of Known P-gp Substrates, Their In Silico and Measured Physicochemical Properties, Renal Recovery (%), In Vitro Transporter Substrate Parameters [17–93]
Table 6.2 Partial List of Known P-gp Inhibitors and Their In Vitro Transporter Substrate Parameters [24, 37, 50, 54, 55, 58, 59, 97–151]
Table 6.3 Classification Scheme of the Drugs Based on the Relevance of P-gp-Mediated Efflux Transport on the Intestinal Drug Absorption In Vivo [201–203]
Table 6.4 Nonsynonymous Nucleotide Polymorphisms in the ABCB1 Gene and Known Ethnic Differences in the Frequency of Genetic Variants
Table 6.5 Partial List of Known BCRP Substrates, Their In Silico and Measured Physicochemical Properties, Renal Recovery (%), In Vitro Transporter Substrate Parameters [18, 25, 35, 60, 87, 223–249]
Table 6.6 Partial List of Known BCRP Inhibitors and Their In Vitro Transporter Substrate Parameters [20, 37, 43, 60, 117, 130, 139, 140, 143, 148–150, 224, 225, 229, 230, 237, 251, 258–318]

CHAPTER 7: IMPACT OF INFLUX TRANSPORTERS ON DRUG ABSORPTION

Table 7.1 Major Uptake Intestinal Transporter Uptake Mechanism, Expression, GIT Segment Expression, Affinity, and Capacity
Table 7.2 Partial List of Known Drugs that are in Clinical Use and Substrates of OATP2B1 [38, 55–75]
Table 7.3 Partial List of Known Inhibitors of OATP2B1 [31, 58, 61–63, 65, 75–94]
Table 7.4 Nonsynonymous Nucleotide Polymorphisms in the SLCO2B1 Gene [102–105]
Table 7.5 Partial List of Known Drugs that are in Clinical Use and Substrates of PepT1 Transporter [123–132]
Table 7.6 Partial List of Known Drugs that are in Clinical Use and Inhibitors of PepT1 Transporter [123–132, 136–141]
Table 7.7 A Partial List of Known Substrates for MCT1 Transporter [158, 159, 169–180]
Table 7.8 A Partial List of Known Inhibitors for MCT1 Transporter [170, 171, 184–186]

CHAPTER 8: EXTENDED CLEARANCE CLASSIFICATION SYSTEM (ECCS) AND ITS UTILITY IN PREDICTING CLEARANCE RATE-DETERMINING STEP IN DRUG DISCOVERY

Table 8.1 Representative Examples per ECCS Class and the Major Transporters and Metabolizing Enzymes Involved in Their Clearance

CHAPTER 9: IN VITRO AND IN SITU APPROACHES TO MEASURE INTESTINAL PERMEABILITY AND EFFLUX TRANSPORTERS

Table 9.1 Similar Correlation Between P_eff Values in Literature-Based Human and Rat Perfusion Values

CHAPTER 10: IN SILICO APPROACHES TO PREDICT INTESTINAL PERMEABILITY

Table 10.1 Common Molecular Descriptor Programs and Their Relevant Information [22, 23]
Table 10.2 Commercial Permeability and In Silico Models and Their Relevant Information [36–40]

CHAPTER 11: IN VIVO PRECLINICAL APPROACHES TO DECONVOLUTE THE CONTRIBUTION OF FIRST-PASS EFFECT FROM ORAL ABSORPTION

Table 11.1 Administration Volumes Considered Good Practice (and Possible Maximum Dose Volume)
Table 11.2 The Pharmacokinetic Parameters of [S,S]-Reboxetine Following 5 mg/kg IV, SC, PO, and IP Dosing to Sprague Dawley Rats (Pfizer Internal Data)

CHAPTER 12: IN VITRO APPROACHES TO ASSESS HEPATIC METABOLISM AND FIRST-PASS EFFECT

Table 12.1 In Vitro and In Vivo Inputs Used to Scale CL_{int,app,scaled} [13, 14]
Table 12.2 Enzyme Abundance and ISEF Correction Values for Known CYP Enzymes

CHAPTER 13: THE UTILITY OF ECCS AS A ROADMAP TO IMPROVE ORAL BIOAVAILABILITY OF NEW MOLECULAR ENTITIES: INDUSTRIAL PERSPECTIVE

Table 13.1 Molecular Weight, Ionization, ECCS Classification, CL_t, CL_h, f_a, f_g, f_h, f, Main Enzymes, Uptake Transporters, and Efflux Transporters Affecting the Disposition of Molecules [4, 14]

Mike S. Lee • Integrated Strategies for Drug Discovery Using Mass Spectrometry

Birendra Pramanik, Mike S. Lee, and Guodong Chen • Characterization of Impurities and Degradants Using Mass Spectrometry

Mike S. Lee and Mingshe Zhu • Mass Spectrometry in Drug Metabolism and Disposition: Basic Principles and Applications

Mike S. Lee and Qin C. Ji • Protein Analysis using Mass Spectrometry: Accelerating Protein Biotherapeutics from Lab to Patient

Ayman F. El-Kattan • Oral Bioavailability Assessment: Basics and Strategies for Drug Discovery and Development

This edition first published 2017

Edition History

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Library of Congress Cataloging-in-Publication Data

Names: El-Kattan, Ayman F., author.

Title: Oral bioavailability assessment : basics and strategies for drug discovery and development / Ayman F. El-Kattan.

Description: Hoboken, NJ : John Wiley & Sons Inc., 2017. | Includes bibliographical references and index.

Identifiers: LCCN 2016055388 (print) | LCCN 2016056137 (ebook) | ISBN 9781118916698 (cloth) | ISBN 9781118916940 (Adobe PDF) | ISBN 9781118916933 (ePub)

Subjects: | MESH: Biological Availability | Drug Evaluation, Preclinical | Toxicokinetics | Administration, Oral

Classification: LCC RS403 (print) | LCC RS403 (ebook) | NLM QV 38 | DDC 615.1/9–dc23

LC record available at https://lccn.loc.gov/2016055388

Cover image:

Figure: Courtesy of Ayman F. El-Kattan

Cover design by Wiley