GOODMAN AND GILMAN'S THE
PHARMACOLOGICAL BASIS OF
THERAPEUTICS
14TH EDITION
• AUTHOR(S)LAURENCE BRUNTON;
BJORN KNOLLMANN
TEST BANK
1
Reference
Section I — Drug Discovery: From Medicinal Plants to
Computer-Aided Drug Design
Stem
A biotech group identifies a natural alkaloid from a medicinal
plant showing potent inhibition of a disease-relevant enzyme in
vitro. The alkaloid is highly lipophilic, binds plasma proteins
extensively, and shows modest metabolic stability in human
,liver microsomes. As a translational pharmacologist advising
lead selection, which property most strongly argues against
advancing this alkaloid as an immediate clinical lead without
modification?
A. High lipophilicity
B. Potent in vitro enzyme inhibition
C. Extensive plasma-protein binding
D. Modest metabolic stability in microsomes
Correct answer
D
Rationale — Correct (D)
Modest metabolic stability in human liver microsomes suggests
rapid hepatic metabolism and likely poor in vivo exposure; this
compromises systemic exposure, shortens half-life, and
complicates dosing. For translation to humans, metabolic
stability is critical to achieve efficacious free drug
concentrations. Chemical modification or prodrug strategies are
typically required to improve metabolic stability before clinical
development.
Rationale — Incorrect
A. High lipophilicity can cause formulation and off-
target/toxicity issues but is addressable through medicinal
chemistry (1–2 sentences).
B. Potent in vitro inhibition is a necessary but insufficient
criterion; potency alone doesn’t ensure appropriate ADME or
safety (1–2 sentences).
,C. Extensive plasma-protein binding reduces free fraction but is
sometimes acceptable if total exposure compensates and free
concentration reaches target (1–2 sentences).
Teaching point
Early metabolic stability predicts in vivo exposure and is crucial
for lead advancement.
Citation
Brunton, L. L., & Knollmann, B. C. (2023). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics (14th ed.). Section I.
2
Reference
Section I — Drug Discovery: From Medicinal Plants to
Computer-Aided Drug Design
Stem
A candidate series was developed by structure-based design
against a validated kinase. In cell assays the compounds inhibit
the kinase but fail to produce the expected phenotype because
they are pumped out of cells by P-glycoprotein (P-gp). For the
medicinal chemist optimizing the series, which strategy most
directly addresses this translational failure?
A. Increase molecular weight to reduce passive diffusion
B. Remove or modify polar groups to increase lipophilicity
C. Reduce recognition motifs for efflux transporters while
preserving potency
, D. Add a permanently charged group to prevent membrane
crossing
Correct answer
C
Rationale — Correct (C)
Reducing structural features recognized by efflux transporters
(P-gp) while maintaining binding affinity addresses the root
cause of intracellular efflux, improving intracellular exposure
and restoring phenotypic effect. This is a targeted medicinal
chemistry optimization guided by transporter structure–activity
relationships.
Rationale — Incorrect
A. Increasing molecular weight often worsens permeability and
may increase P-gp recognition (1–2 sentences).
B. Increasing lipophilicity can increase passive uptake but may
also increase P-gp efflux and toxicity (1–2 sentences).
D. Adding a permanent charge will typically reduce passive
membrane permeation and likely worsen intracellular access
(1–2 sentences).
Teaching point
Optimize structures to avoid efflux recognition to achieve
intracellular target engagement.
Citation
Brunton, L. L., & Knollmann, B. C. (2023). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics (14th ed.). Section I.
PHARMACOLOGICAL BASIS OF
THERAPEUTICS
14TH EDITION
• AUTHOR(S)LAURENCE BRUNTON;
BJORN KNOLLMANN
TEST BANK
1
Reference
Section I — Drug Discovery: From Medicinal Plants to
Computer-Aided Drug Design
Stem
A biotech group identifies a natural alkaloid from a medicinal
plant showing potent inhibition of a disease-relevant enzyme in
vitro. The alkaloid is highly lipophilic, binds plasma proteins
extensively, and shows modest metabolic stability in human
,liver microsomes. As a translational pharmacologist advising
lead selection, which property most strongly argues against
advancing this alkaloid as an immediate clinical lead without
modification?
A. High lipophilicity
B. Potent in vitro enzyme inhibition
C. Extensive plasma-protein binding
D. Modest metabolic stability in microsomes
Correct answer
D
Rationale — Correct (D)
Modest metabolic stability in human liver microsomes suggests
rapid hepatic metabolism and likely poor in vivo exposure; this
compromises systemic exposure, shortens half-life, and
complicates dosing. For translation to humans, metabolic
stability is critical to achieve efficacious free drug
concentrations. Chemical modification or prodrug strategies are
typically required to improve metabolic stability before clinical
development.
Rationale — Incorrect
A. High lipophilicity can cause formulation and off-
target/toxicity issues but is addressable through medicinal
chemistry (1–2 sentences).
B. Potent in vitro inhibition is a necessary but insufficient
criterion; potency alone doesn’t ensure appropriate ADME or
safety (1–2 sentences).
,C. Extensive plasma-protein binding reduces free fraction but is
sometimes acceptable if total exposure compensates and free
concentration reaches target (1–2 sentences).
Teaching point
Early metabolic stability predicts in vivo exposure and is crucial
for lead advancement.
Citation
Brunton, L. L., & Knollmann, B. C. (2023). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics (14th ed.). Section I.
2
Reference
Section I — Drug Discovery: From Medicinal Plants to
Computer-Aided Drug Design
Stem
A candidate series was developed by structure-based design
against a validated kinase. In cell assays the compounds inhibit
the kinase but fail to produce the expected phenotype because
they are pumped out of cells by P-glycoprotein (P-gp). For the
medicinal chemist optimizing the series, which strategy most
directly addresses this translational failure?
A. Increase molecular weight to reduce passive diffusion
B. Remove or modify polar groups to increase lipophilicity
C. Reduce recognition motifs for efflux transporters while
preserving potency
, D. Add a permanently charged group to prevent membrane
crossing
Correct answer
C
Rationale — Correct (C)
Reducing structural features recognized by efflux transporters
(P-gp) while maintaining binding affinity addresses the root
cause of intracellular efflux, improving intracellular exposure
and restoring phenotypic effect. This is a targeted medicinal
chemistry optimization guided by transporter structure–activity
relationships.
Rationale — Incorrect
A. Increasing molecular weight often worsens permeability and
may increase P-gp recognition (1–2 sentences).
B. Increasing lipophilicity can increase passive uptake but may
also increase P-gp efflux and toxicity (1–2 sentences).
D. Adding a permanent charge will typically reduce passive
membrane permeation and likely worsen intracellular access
(1–2 sentences).
Teaching point
Optimize structures to avoid efflux recognition to achieve
intracellular target engagement.
Citation
Brunton, L. L., & Knollmann, B. C. (2023). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics (14th ed.). Section I.
