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Introduction to Drug metabolism: case studies 
for its impacts on drug discovery and development 
Zhoupeng Zhang 
Dept of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism 
Merck Research Laboratories 
Sino-American Pharmaceutical Professionals Association (SAPA) 
– A lecture for Medicinal Chemists 
(October 2, 2014)
R&D Spending trend of 8 US pharmaceutical companies* 
35 
30 
25 
20 
15 
10 
5 
0 
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 
R&D Spending ($ billions) 
C&E News July 2, 2007 issue 
* Abbott, BMS, Eli Lilly, J&J, Merck, Pfizer, Schering-Plough, and Wyeth.
Numbers of drugs approved by FDA (1996 – 2007) 
Hughes B, Nature Reviews Drug Discovery 7, 107, 2008
Drug development processes 
Dickson M and Gagnon J P, Nature Reviews Drug Discovery 3, 417, 2004
Success rate by phase of development 
Kola I and Landis J, Nature Reviews Drug Discovery 3, 711, 2004
Trends in times for development of a NCE 
Dickson M and Gagnon J P, Nature Reviews Drug Discovery 3, 417, 2004
Estimated cost and time for a NCE 
• > $ 800 millions ! 
• ~ 8 – 12 years ! 
Dickson M and Gagnon J P, Nature Reviews Drug Discovery 3, 417, 2004
Reasons for termination of drug candidates in development 
Human Human Animal Lack of 
PK AEs Toxicity efficacy 
Years Financial Others 
1964-1985 39% 10% 11% 29% 6% 5% 
Prentis, R.A., 1988
Reasons for termination of drug candidates in development 
Kola I and Landis J, Nature Reviews Drug Discovery 3, 711, 2004
Involvement of drug metabolism in drug 
discovery and development processes
ADME 
Drug 
Absorption 
Distribution 
Metabolism 
Excretion Elimination 
Disposition
ADME 
Absorption – Process by which drug proceeds from site of 
administration to the general circulation (plasma) 
Disposition – All processes after absorption of drug 
- Distribution – Reversible transfer of drug to and from the 
circulation 
- Elimination – Irreversible loss of drug from the circulation 
- Metabolism – Conversion of drug to another chemical 
species 
- Excretion – Irreversible loss of unchanged drug
ADME 
Drug release & 
dissolution 
Absorption Drug in systemic 
circulation 
Drug in 
tissues 
Metabolism & 
Excretion 
Types of metabolism: 
- Phase I metabolism – oxidation, reduction and hydrolysis. 
- Phase II metabolism – glucuronidation, sulfation, conjugations 
with GSH, amino acids, acetylation, 
methylation, etc. 
- Phase III (?) metabolism – transport of drugs
Metabolism and drug design 
• Hard drugs – non-metabolizable. They are 
excreted primarily through either the bile or 
kidney. 
• Soft drugs are pharmacologically active, and 
undergo a predictable and controllable 
metabolism to nontoxic and inactive 
metabolites. 
• Active metabolites are pharmacologically 
active, and are generated from metabolism. 
• Not all metabolites are nontoxic. 
Academic interest
Pharmacokinetics and drug design 
• Absorption - influenced by solubility, lipophilicity 
(cell peameability), involvement of transporters, etc. 
• Prodrug – inactive prodrug is converted to 
an active metabolite via in vivo metabolism. 
• Distribution - influenced by lipophilicity, 
protein binding, P-glycoprotein, etc. 
• Plasma half-life – determined by the volume of 
distribution and elimination clearance.
DMPK in drug development 
• In vitro studies of drug metabolism 
- Determination of metabolic pathways 
- Identification of drug-metabolizing enzymes 
- Drug-drug interaction potential 
- prediction of in vivo metabolic clearance 
• In vitro studies of drug absorption 
• In vitro studies of protein binding 
• Polymorphism in drug metabolism
Requirements of a successful new drug 
• Satisfies an unmet medical need 
• Exhibits superiority over existing treatments 
– new mechanism of action 
– improved potency or selectivity 
– improved safety profile 
– superior pharmacokinetics 
– improved metabolic characteristics
Criteria for an “ideal” drug from a 
drug metabolism point of view 
• Good aqueous solubility (oral absorption / i.v. formulation) 
• Acceptable (linear) PK for intended route / frequency of dosing 
• “Balanced” clearance (renal, biliary, metabolism) 
• Oxidative metabolism catalyzed by several enzymes (CYPs) 
• Minimal dependence on polymorphically-expressed enzymes 
• Low propensity to inhibit drug-metabolizing 
enzymes/transporters 
• Low first-pass effect, high oral bioavailability 
• Moderate plasma protein binding 
• Minimal conversion to chemically reactive metabolites 
– Concerns over potential toxicity
Criteria for an “ideal” drug from a 
drug metabolism point of view? 
• Good aqueous solubility (oral absorption / i.v. formulation) 
• Acceptable (linear) PK for intended route / frequency of dosing 
• “Balanced” clearance (renal, biliary, metabolism) 
• Oxidative metabolism catalyzed by several enzymes (CYPs) 
• Minimal dependence on polymorphically-expressed enzymes 
• Low propensity to inhibit drug-metabolizing 
enzymes/transporters 
• Low first-pass effect, high oral bioavailability 
• Moderate plasma protein binding 
• Minimal conversion to chemically reactive metabolites 
– Concern over potential toxicity 
Metabolite identification
Metabolite Identification and Profiling in Drug Design
Outline 
1. Optimization of Pharmacokinetics (PK) and 
Pharmacokinetics (PD) Properties 
- Identification of Metabolic Soft Spots 
- Identification of Active Metabolites 
2. Improvement of Safety Profile 
- Minimization of Bioactivation Potential 
- Minimization of Drug-drug Interaction and Polymorphic 
Drug Metabolizing Enzyme-related Risk 
- Evaluation of Species Differences in Metabolism
1. Optimization of PK and PD Properties 
- Identification of Metabolic Soft Spots 
• After oral administration, drugs absorbed by intestine pass through the gut wall and liver 
prior to reaching the systemic circulation. 
• GI tract and liver contain high levels of drug metabolizing enzymes, and extensive metabolism 
in GI tract and liver following oral dosing (first-pass metabolism) would lead to low oral 
bioavailability, and short t1/2 (drug coverage shorter than a desired duration). 
• Optimize the rate of metabolism of an NCE would eventually realize its PD effect both in 
animal models and humans. 
• Liver often is the major organ responsible for drug metabolism. Thus, metabolic stability 
studies generally are performed in vitro with liver microsomes/hepatocytes for screening. 
• In vitro metabolite profiling studies of selected metabolically unstable compounds are 
conducted in order to identify metabolic soft spots which represent metabolically liable 
functional groups or the positions on a functional group (likely responsible for fast clearance ) 
based on the characterization of major metabolites. 
• Blockage of metabolic soft spots via chemical modification of compounds is one of the 
approaches to improve metabolic stability of compounds, particularly when metabolism is 
catalyzed by P450s, leading to the improved PK properties (t1/2 and oral bioavailability).
Case #1: Metabolic stability of compound A (1 μM) in rat liver 
microsomes (0.5 mg protein/mL) in the presence of NADPH 
100 
10 
0 10 20 30 45 
Time (min) 
% of parent remaining
Metabolynx report of metabolite profile of compound A 
M1 
Cpd A M1 
Cpd A 
in incubation with rat liver microsomes
Radiochromatogram of a sample from incubation of 
[3H]compound A with rat liver microsomes. 
M1 
Compound A 
Rat liver microsomes (60 min) 
Time (min) 
Radioactivity (DPM)
Case #2: Identification of Metabolic Soft Spots of FK788 
O 
HO O 
O 
O 
N 
OH 
FK788 
• A prostanoid PGI2 receptor agonist. 
• t1/2: 1.5 h in human, 1.8 h in rat.
O 
HO O 
O 
N 
OH 
O 
FK788 
O 
HO O 
O 
N 
OH 
O 
M1 
OH 
O 
HO O 
O 
N 
OH 
O 
Compound 1 
F 
O 
HO O 
OH F 
O 
N 
O 
F 
Compound 2 
FK788 Compound 1 Compound 2 
Clint: 31.9 mL/min/kg Clint: 10.3 mL/min/kg Clint: 4.6 mL/min/kg 
(In RLM) 
AUC: 601 ng*h/mL AUC: 961 ng*h/mL AUC: 1607 ng*h/mL 
F: 9.6% F: 19.2% F: 29.5% 
T1/2: 1.8 h T1/2: 1.6 h T1/2: 3.0 h 
(In rats)
1. Optimization of PK and PD Properties 
- Identification of Active Metabolites 
• Drug metabolites could have no pharmacological activity or the activity less than, or 
equivalent to, or more potent than that of the parent molecules. 
• Metabolites with equivalent or better pharmacological activity are active metabolites. 
• Metabolite identification and profiling identifies a new structural template with 
increased potency/selectivity or reduced adverse. 
• A hint of the presence of active metabolite may come from a lack of PK-PD 
correlation wherein the in vivo efficacy exceeds the in vitro potency of an NCE. 
• Consequently, the NCE would be characterized for its metabolism, including 
identification of major circulating metabolites in preclinical PD models. 
• The metabolites would be synthesized and tested for their potency against the 
pharmacological target of interest.
Identification of Active Metabolites – a Case Study 
N 
O 
O 
NH 
O 
Cl 
LM-4108 
N 
O 
O 
OH O 
NH 
O 
Cl 
2'-Hydroxy-LM-4108 
N 
O 
O 
NH 
O 
Cl 
2'-Oxo-LM-4108 
+ 
• A COX-2 inhibitor. 
• Two major metabolites detected in LM of mouse, rat and human, 
• Metabolites are equipotent as LM-4108 in the in vitro assays 
• Metabolites are also present in plasma of rats, may contribute to 
the PD effects. 
• Further investigation of these two metabolites is warranted.
Acetaminophen 
HO 
HN O 
Phenacetin 
O 
HN 
O 
HN 
O 
Acetanilide
N 
Cl 
O O 
N 
Loratadine (Claritin) 
N 
Cl 
HN 
Descarboethoxyloratadine 
(Desloratadine) 
IC50 for IL-6 (nM) : 300 0.0026 
IC50 for IL-8 (nM) : 200 0.001 
Clinical dose (mg): 10 5
2. Improvement of Safety Profile 
- Minimization of Bioactivation Potential
O 
O 
O 
S Protein S Protein 
OH 
S Protein 
OH 
OH 
S Protein 
O 
S Protein 
OH 
H2O 
S Protein 
Formation of drug-protein adducts 
Idyosyncratic drug reactions Tissue damages
Biomarkers commonly used for studying the 
mechanism of metabolic activation of drugs 
O N H O 
S H NH 
O 
OH 
O 
OH 
NH2 
HO O 
S H NH 
O 
CN-O 
Glutathione (GSH) N-acetylcysteine (NAc) Cyanide 
O 
O 
- R 
S R S 
OH 
OH 
R S 
OH 
Detection by LC/MS/MS 
and NMR 
-CN 
CN 
+ 
N N
Minimization of Bioactivation Potential – Case Study 
R 
O 
R OH 
OH 
R O 
O 
[O] H2O 
[O] 
R OH 
OH 
GSH 
GS 
R 
F 
O 
R 
OH 
SG 
-HF 
R O 
SG 
[O] 
R OH 
SG 
GSH 
F F 
F 
F F 
R 
Compound 3 
1490 pmol/mg protein 
in rat liver microsomes 
R F 
F 
Compound 4 
841 pmol/mg protein 
in rat liver microsomes
Covalent Protein Binding of [3H]Compounds in Liver Microsomes 
of Rats (RLM) and human (HLM) (pmol/mg protein) 
R 
Compound 3 
R F 
F 
Compound 4 
R N 
Compound 5 
R N 
Cl 
Compound 6 
R N 
CF3 
Compound 7 
RLM 1490 841 535 190 111 
HLM 3870 1690 911 303 88
2. Improvement of Safety Profile 
- Minimization of Drug-Drug Interaction and Polymorphic 
Drug Metabolizing Enzyme-related Risk 
• Phenotyping metabolizing enzyme(s): 
- In vitro metabolite profiling with recombinant human enzymes 
- In vitro metabolite profiling with human liver microsomes in the presence of 
selective chemical inhibitors and/or antibodies. 
• If a single and/or polymorphic enzyme is responsible for the clearance of an NCE: 
- A clinical DDI study is warranted; 
- If there is a significant safety concern, the development of the NCE could be 
terminated prior to the clinical study. 
• Thus, it is important to minimize DDI potentials and the dependence of 
metabolism on a single polymorphic enzyme early in drug discovery.
Minimization of Drug-drug Interaction and Polymorphic 
Drug Metabolizing Enzyme-related Risk – a Case Study 
HN 
O OH 
O 
Metoprolol 
65% 
10% 
10% 
• A beta-1-adrenoceptor antagonist (blocker) for hypertension. 
• Low oral bioavailability and short duration of action in vivo, 
due to extensive hepatic metabolism. 
• Metabolized mainly by CYP2D6, a polymorphic enzyme. 
• A 100-fold variation for plasma exposure of metoprolol and its 
α-OH metabolite and up to 36-fold difference in Cl in 91 patients 
with cardiovascular diseases.
HN 
O OH 
O 
Betaxolol 
• Slow metabolism was observed. 
• Metabolized by CYP2D6 and CYP1A2, and CYP2D6 only accounts 
for 40% of metabolism in human. 
• Betaxolol posses a reduced dependence of polymorphic 
CYP2D6-mediated metabolism, and therefore may exhibit a smaller 
individual variation in its clinical PK as compared to metoprolol.
2. Improvement of Safety Profile 
- Evaluation of Species Differences in Metabolism 
• For a drug candidate, it is important to know which preclinical species 
is capable of producing metabolite profiles similar to that of humans. 
• In vitro and in vivo metabolite profiling provides the data that enable 
a comparison of the metabolic fate of compounds in different species, 
allowing for selection of an appropriate preclinical model for: 
- human pharmacokinetic prediction, and 
- preclinical safety evaluation 
• If significant difference of metabolism is observed between human and 
an animal species, or a human specific major metabolite is detected, 
there may be a need to perform additional studies to evaluate the 
safety of the metabolite.
Evaluation of Species Differences in Metabolism – a Case Study 
O 
O 
N 
R1 
R2 
R4 
R3 
CDP-840 
O 
O 
N 
R1 
R2 
R4 
R3 
M3 OH 
O 
O 
N+ 
R1 
R2 
R4 
R3 
M2 
Gluc 
+ 
• An inhibitor of phosphodiesterase type IV Major in HH, not in RH Major in RLM, 
O 
O 
N 
R1 
R2 
R4 
R3 
Cl 
CT2412 
O 
O 
N+ 
R1 
R2 
R4 
R3 
O-CT2481 
Cl 
Not in HLM and HH. 
• Similar metabolite profiles in LM 
and HP from various species
Workflow for a Centralized Metabolite Identification Assay 
On-line submission for 
MetID of compounds 
Automated in vitro 
incubations using a 
robotic liquid handler 
Submission of a consolidated 
list of compounds to a central 
compound repository 
DMPK scientists 
Delivery of compounds 
in a 96-well plate 
Dilution of compounds 
in 96-well plate 
MetID software for post 
acquisition processing 
and reporting 
LC-accurate 
MS (HRMS) 
runs
Major Utilities of Metabolite Identification and Profiling in Drug Discovery 
• Minimization of bioactivation potential 
• Improvement of PK and PD 
Lead identification NCE characterization 
Hit Lead 
Lead optimization 
NCE 
candidate 
NCE 
Lead characterization 
• Finding of active metabolite 
or new structural template 
• Selection of preclinical safety species 
• Finding of active metabolite 
or new structural template 
• Minimization of DDI potential 
• Selection of preclinical safety species
Role of DMPK in drug development 
Baillie T A, Chem Res Toxicol 21, 129, 2008
Roles of DMPK 
in drug discovery and development 
Baillie T A, Chem Res Toxicol 21, 129, 2008
Acknowledgements 
Mingshe Zhu, Wei Tang 
Colleagues at Merck

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Introduction to drug metabolism case studies for its impacts on drug discovery and development

  • 1. Introduction to Drug metabolism: case studies for its impacts on drug discovery and development Zhoupeng Zhang Dept of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism Merck Research Laboratories Sino-American Pharmaceutical Professionals Association (SAPA) – A lecture for Medicinal Chemists (October 2, 2014)
  • 2. R&D Spending trend of 8 US pharmaceutical companies* 35 30 25 20 15 10 5 0 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 R&D Spending ($ billions) C&E News July 2, 2007 issue * Abbott, BMS, Eli Lilly, J&J, Merck, Pfizer, Schering-Plough, and Wyeth.
  • 3. Numbers of drugs approved by FDA (1996 – 2007) Hughes B, Nature Reviews Drug Discovery 7, 107, 2008
  • 4. Drug development processes Dickson M and Gagnon J P, Nature Reviews Drug Discovery 3, 417, 2004
  • 5. Success rate by phase of development Kola I and Landis J, Nature Reviews Drug Discovery 3, 711, 2004
  • 6. Trends in times for development of a NCE Dickson M and Gagnon J P, Nature Reviews Drug Discovery 3, 417, 2004
  • 7. Estimated cost and time for a NCE • > $ 800 millions ! • ~ 8 – 12 years ! Dickson M and Gagnon J P, Nature Reviews Drug Discovery 3, 417, 2004
  • 8. Reasons for termination of drug candidates in development Human Human Animal Lack of PK AEs Toxicity efficacy Years Financial Others 1964-1985 39% 10% 11% 29% 6% 5% Prentis, R.A., 1988
  • 9. Reasons for termination of drug candidates in development Kola I and Landis J, Nature Reviews Drug Discovery 3, 711, 2004
  • 10. Involvement of drug metabolism in drug discovery and development processes
  • 11. ADME Drug Absorption Distribution Metabolism Excretion Elimination Disposition
  • 12. ADME Absorption – Process by which drug proceeds from site of administration to the general circulation (plasma) Disposition – All processes after absorption of drug - Distribution – Reversible transfer of drug to and from the circulation - Elimination – Irreversible loss of drug from the circulation - Metabolism – Conversion of drug to another chemical species - Excretion – Irreversible loss of unchanged drug
  • 13. ADME Drug release & dissolution Absorption Drug in systemic circulation Drug in tissues Metabolism & Excretion Types of metabolism: - Phase I metabolism – oxidation, reduction and hydrolysis. - Phase II metabolism – glucuronidation, sulfation, conjugations with GSH, amino acids, acetylation, methylation, etc. - Phase III (?) metabolism – transport of drugs
  • 14. Metabolism and drug design • Hard drugs – non-metabolizable. They are excreted primarily through either the bile or kidney. • Soft drugs are pharmacologically active, and undergo a predictable and controllable metabolism to nontoxic and inactive metabolites. • Active metabolites are pharmacologically active, and are generated from metabolism. • Not all metabolites are nontoxic. Academic interest
  • 15. Pharmacokinetics and drug design • Absorption - influenced by solubility, lipophilicity (cell peameability), involvement of transporters, etc. • Prodrug – inactive prodrug is converted to an active metabolite via in vivo metabolism. • Distribution - influenced by lipophilicity, protein binding, P-glycoprotein, etc. • Plasma half-life – determined by the volume of distribution and elimination clearance.
  • 16. DMPK in drug development • In vitro studies of drug metabolism - Determination of metabolic pathways - Identification of drug-metabolizing enzymes - Drug-drug interaction potential - prediction of in vivo metabolic clearance • In vitro studies of drug absorption • In vitro studies of protein binding • Polymorphism in drug metabolism
  • 17. Requirements of a successful new drug • Satisfies an unmet medical need • Exhibits superiority over existing treatments – new mechanism of action – improved potency or selectivity – improved safety profile – superior pharmacokinetics – improved metabolic characteristics
  • 18. Criteria for an “ideal” drug from a drug metabolism point of view • Good aqueous solubility (oral absorption / i.v. formulation) • Acceptable (linear) PK for intended route / frequency of dosing • “Balanced” clearance (renal, biliary, metabolism) • Oxidative metabolism catalyzed by several enzymes (CYPs) • Minimal dependence on polymorphically-expressed enzymes • Low propensity to inhibit drug-metabolizing enzymes/transporters • Low first-pass effect, high oral bioavailability • Moderate plasma protein binding • Minimal conversion to chemically reactive metabolites – Concerns over potential toxicity
  • 19. Criteria for an “ideal” drug from a drug metabolism point of view? • Good aqueous solubility (oral absorption / i.v. formulation) • Acceptable (linear) PK for intended route / frequency of dosing • “Balanced” clearance (renal, biliary, metabolism) • Oxidative metabolism catalyzed by several enzymes (CYPs) • Minimal dependence on polymorphically-expressed enzymes • Low propensity to inhibit drug-metabolizing enzymes/transporters • Low first-pass effect, high oral bioavailability • Moderate plasma protein binding • Minimal conversion to chemically reactive metabolites – Concern over potential toxicity Metabolite identification
  • 20. Metabolite Identification and Profiling in Drug Design
  • 21. Outline 1. Optimization of Pharmacokinetics (PK) and Pharmacokinetics (PD) Properties - Identification of Metabolic Soft Spots - Identification of Active Metabolites 2. Improvement of Safety Profile - Minimization of Bioactivation Potential - Minimization of Drug-drug Interaction and Polymorphic Drug Metabolizing Enzyme-related Risk - Evaluation of Species Differences in Metabolism
  • 22. 1. Optimization of PK and PD Properties - Identification of Metabolic Soft Spots • After oral administration, drugs absorbed by intestine pass through the gut wall and liver prior to reaching the systemic circulation. • GI tract and liver contain high levels of drug metabolizing enzymes, and extensive metabolism in GI tract and liver following oral dosing (first-pass metabolism) would lead to low oral bioavailability, and short t1/2 (drug coverage shorter than a desired duration). • Optimize the rate of metabolism of an NCE would eventually realize its PD effect both in animal models and humans. • Liver often is the major organ responsible for drug metabolism. Thus, metabolic stability studies generally are performed in vitro with liver microsomes/hepatocytes for screening. • In vitro metabolite profiling studies of selected metabolically unstable compounds are conducted in order to identify metabolic soft spots which represent metabolically liable functional groups or the positions on a functional group (likely responsible for fast clearance ) based on the characterization of major metabolites. • Blockage of metabolic soft spots via chemical modification of compounds is one of the approaches to improve metabolic stability of compounds, particularly when metabolism is catalyzed by P450s, leading to the improved PK properties (t1/2 and oral bioavailability).
  • 23. Case #1: Metabolic stability of compound A (1 μM) in rat liver microsomes (0.5 mg protein/mL) in the presence of NADPH 100 10 0 10 20 30 45 Time (min) % of parent remaining
  • 24. Metabolynx report of metabolite profile of compound A M1 Cpd A M1 Cpd A in incubation with rat liver microsomes
  • 25. Radiochromatogram of a sample from incubation of [3H]compound A with rat liver microsomes. M1 Compound A Rat liver microsomes (60 min) Time (min) Radioactivity (DPM)
  • 26. Case #2: Identification of Metabolic Soft Spots of FK788 O HO O O O N OH FK788 • A prostanoid PGI2 receptor agonist. • t1/2: 1.5 h in human, 1.8 h in rat.
  • 27. O HO O O N OH O FK788 O HO O O N OH O M1 OH O HO O O N OH O Compound 1 F O HO O OH F O N O F Compound 2 FK788 Compound 1 Compound 2 Clint: 31.9 mL/min/kg Clint: 10.3 mL/min/kg Clint: 4.6 mL/min/kg (In RLM) AUC: 601 ng*h/mL AUC: 961 ng*h/mL AUC: 1607 ng*h/mL F: 9.6% F: 19.2% F: 29.5% T1/2: 1.8 h T1/2: 1.6 h T1/2: 3.0 h (In rats)
  • 28. 1. Optimization of PK and PD Properties - Identification of Active Metabolites • Drug metabolites could have no pharmacological activity or the activity less than, or equivalent to, or more potent than that of the parent molecules. • Metabolites with equivalent or better pharmacological activity are active metabolites. • Metabolite identification and profiling identifies a new structural template with increased potency/selectivity or reduced adverse. • A hint of the presence of active metabolite may come from a lack of PK-PD correlation wherein the in vivo efficacy exceeds the in vitro potency of an NCE. • Consequently, the NCE would be characterized for its metabolism, including identification of major circulating metabolites in preclinical PD models. • The metabolites would be synthesized and tested for their potency against the pharmacological target of interest.
  • 29. Identification of Active Metabolites – a Case Study N O O NH O Cl LM-4108 N O O OH O NH O Cl 2'-Hydroxy-LM-4108 N O O NH O Cl 2'-Oxo-LM-4108 + • A COX-2 inhibitor. • Two major metabolites detected in LM of mouse, rat and human, • Metabolites are equipotent as LM-4108 in the in vitro assays • Metabolites are also present in plasma of rats, may contribute to the PD effects. • Further investigation of these two metabolites is warranted.
  • 30. Acetaminophen HO HN O Phenacetin O HN O HN O Acetanilide
  • 31. N Cl O O N Loratadine (Claritin) N Cl HN Descarboethoxyloratadine (Desloratadine) IC50 for IL-6 (nM) : 300 0.0026 IC50 for IL-8 (nM) : 200 0.001 Clinical dose (mg): 10 5
  • 32. 2. Improvement of Safety Profile - Minimization of Bioactivation Potential
  • 33. O O O S Protein S Protein OH S Protein OH OH S Protein O S Protein OH H2O S Protein Formation of drug-protein adducts Idyosyncratic drug reactions Tissue damages
  • 34. Biomarkers commonly used for studying the mechanism of metabolic activation of drugs O N H O S H NH O OH O OH NH2 HO O S H NH O CN-O Glutathione (GSH) N-acetylcysteine (NAc) Cyanide O O - R S R S OH OH R S OH Detection by LC/MS/MS and NMR -CN CN + N N
  • 35. Minimization of Bioactivation Potential – Case Study R O R OH OH R O O [O] H2O [O] R OH OH GSH GS R F O R OH SG -HF R O SG [O] R OH SG GSH F F F F F R Compound 3 1490 pmol/mg protein in rat liver microsomes R F F Compound 4 841 pmol/mg protein in rat liver microsomes
  • 36. Covalent Protein Binding of [3H]Compounds in Liver Microsomes of Rats (RLM) and human (HLM) (pmol/mg protein) R Compound 3 R F F Compound 4 R N Compound 5 R N Cl Compound 6 R N CF3 Compound 7 RLM 1490 841 535 190 111 HLM 3870 1690 911 303 88
  • 37. 2. Improvement of Safety Profile - Minimization of Drug-Drug Interaction and Polymorphic Drug Metabolizing Enzyme-related Risk • Phenotyping metabolizing enzyme(s): - In vitro metabolite profiling with recombinant human enzymes - In vitro metabolite profiling with human liver microsomes in the presence of selective chemical inhibitors and/or antibodies. • If a single and/or polymorphic enzyme is responsible for the clearance of an NCE: - A clinical DDI study is warranted; - If there is a significant safety concern, the development of the NCE could be terminated prior to the clinical study. • Thus, it is important to minimize DDI potentials and the dependence of metabolism on a single polymorphic enzyme early in drug discovery.
  • 38. Minimization of Drug-drug Interaction and Polymorphic Drug Metabolizing Enzyme-related Risk – a Case Study HN O OH O Metoprolol 65% 10% 10% • A beta-1-adrenoceptor antagonist (blocker) for hypertension. • Low oral bioavailability and short duration of action in vivo, due to extensive hepatic metabolism. • Metabolized mainly by CYP2D6, a polymorphic enzyme. • A 100-fold variation for plasma exposure of metoprolol and its α-OH metabolite and up to 36-fold difference in Cl in 91 patients with cardiovascular diseases.
  • 39. HN O OH O Betaxolol • Slow metabolism was observed. • Metabolized by CYP2D6 and CYP1A2, and CYP2D6 only accounts for 40% of metabolism in human. • Betaxolol posses a reduced dependence of polymorphic CYP2D6-mediated metabolism, and therefore may exhibit a smaller individual variation in its clinical PK as compared to metoprolol.
  • 40. 2. Improvement of Safety Profile - Evaluation of Species Differences in Metabolism • For a drug candidate, it is important to know which preclinical species is capable of producing metabolite profiles similar to that of humans. • In vitro and in vivo metabolite profiling provides the data that enable a comparison of the metabolic fate of compounds in different species, allowing for selection of an appropriate preclinical model for: - human pharmacokinetic prediction, and - preclinical safety evaluation • If significant difference of metabolism is observed between human and an animal species, or a human specific major metabolite is detected, there may be a need to perform additional studies to evaluate the safety of the metabolite.
  • 41. Evaluation of Species Differences in Metabolism – a Case Study O O N R1 R2 R4 R3 CDP-840 O O N R1 R2 R4 R3 M3 OH O O N+ R1 R2 R4 R3 M2 Gluc + • An inhibitor of phosphodiesterase type IV Major in HH, not in RH Major in RLM, O O N R1 R2 R4 R3 Cl CT2412 O O N+ R1 R2 R4 R3 O-CT2481 Cl Not in HLM and HH. • Similar metabolite profiles in LM and HP from various species
  • 42. Workflow for a Centralized Metabolite Identification Assay On-line submission for MetID of compounds Automated in vitro incubations using a robotic liquid handler Submission of a consolidated list of compounds to a central compound repository DMPK scientists Delivery of compounds in a 96-well plate Dilution of compounds in 96-well plate MetID software for post acquisition processing and reporting LC-accurate MS (HRMS) runs
  • 43. Major Utilities of Metabolite Identification and Profiling in Drug Discovery • Minimization of bioactivation potential • Improvement of PK and PD Lead identification NCE characterization Hit Lead Lead optimization NCE candidate NCE Lead characterization • Finding of active metabolite or new structural template • Selection of preclinical safety species • Finding of active metabolite or new structural template • Minimization of DDI potential • Selection of preclinical safety species
  • 44. Role of DMPK in drug development Baillie T A, Chem Res Toxicol 21, 129, 2008
  • 45. Roles of DMPK in drug discovery and development Baillie T A, Chem Res Toxicol 21, 129, 2008
  • 46. Acknowledgements Mingshe Zhu, Wei Tang Colleagues at Merck