GOODMAN AND GILMAN'S THE
PHARMACOLOGICAL BASIS OF
THERAPEUTICS
14TH EDITION
• AUTHOR(S)LAURENCE BRUNTON;
BJORN KNOLLMANN
TEST BANK
1
Reference
Ch. 1 — Drug Discovery: From Medicinal Plants to Computer-
Aided Drug Design
Stem
A 62-year-old patient with stage 3 chronic kidney disease (CKD)
is enrolled in a phase I trial of a novel small molecule discovered
from a plant alkaloid scaffold. Preclinical lead optimization
added a polar side chain to reduce lipophilicity and predicted
renal clearance. Which design decision most likely reduces risk
,of toxic accumulation in this CKD patient while preserving oral
bioavailability?
A. Increase basicity to enhance passive tubular reabsorption.
B. Add a glucuronidable phenolic group to increase phase II
clearance.
C. Substitute a metabolically stable halogen to block
metabolism.
D. Increase lipophilicity to enhance membrane permeation.
Correct answer
B
Rationales
Correct (B): Adding a glucuronidable phenolic group promotes
phase II conjugation (glucuronidation), producing polar
metabolites eliminated more via biliary/renal routes. In CKD,
enhancing conjugation reduces parent-drug exposure and limits
accumulation; careful PK studies are still required to confirm
metabolite clearance.
Incorrect (A): Increasing basicity often enhances tubular
reabsorption and can raise renal retention and accumulation in
CKD.
Incorrect (C): Introducing a metabolically stable halogen
reduces metabolic clearance and increases half-life —
undesirable in renal impairment.
Incorrect (D): Increasing lipophilicity can improve permeability
but generally raises volume of distribution and decreases renal
elimination, risking accumulation.
,Teaching point
Design polar, conjugation-prone groups to favor safe elimination
in renal impairment.
Citation
Brunton, L. L., & Knollmann, B. C. (2023). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics (14th ed.). Ch. 1.
2
Reference
Ch. 1 — Target Identification & Validation
Stem
A biotech company prioritizes targets for a neurodegenerative
disease. Two candidate proteins are identified: Protein X (highly
disease-associated but expressed ubiquitously) and Protein Y
(disease-specific but with low druggability by small molecules).
From a translational risk-benefit perspective, which strategy
best balances efficacy and safety?
A. Prioritize Protein X because ubiquitous expression increases
likelihood of therapeutic effect.
B. Prioritize Protein Y and invest in biologics or modality
engineering despite low small-molecule druggability.
C. Abandon both and target a downstream signaling enzyme to
avoid on-target toxicity.
D. Use a high-throughput screen to find covalent small-
molecule binders to Protein Y.
, Correct answer
B
Rationales
Correct (B): A disease-specific target (Protein Y) lowers on-
target systemic toxicity; investing in alternative modalities
(antibodies, ASOs) is a rational translational choice when small-
molecule druggability is low. This balances efficacy with safety
for chronic neurodegenerative therapy.
Incorrect (A): Ubiquitous expression of Protein X raises high risk
of systemic adverse effects despite strong disease association.
Incorrect (C): Targeting downstream enzymes may dilute
efficacy and miss upstream disease mechanisms; not
necessarily safer without validation.
Incorrect (D): Seeking covalent small molecules for a poorly
druggable target is high risk and may produce irreversible off-
target toxicity.
Teaching point
Favor disease-specific targets; choose modalities that fit target
druggability and safety profile.
Citation
Brunton, L. L., & Knollmann, B. C. (2023). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics (14th ed.). Ch. 1.
3
PHARMACOLOGICAL BASIS OF
THERAPEUTICS
14TH EDITION
• AUTHOR(S)LAURENCE BRUNTON;
BJORN KNOLLMANN
TEST BANK
1
Reference
Ch. 1 — Drug Discovery: From Medicinal Plants to Computer-
Aided Drug Design
Stem
A 62-year-old patient with stage 3 chronic kidney disease (CKD)
is enrolled in a phase I trial of a novel small molecule discovered
from a plant alkaloid scaffold. Preclinical lead optimization
added a polar side chain to reduce lipophilicity and predicted
renal clearance. Which design decision most likely reduces risk
,of toxic accumulation in this CKD patient while preserving oral
bioavailability?
A. Increase basicity to enhance passive tubular reabsorption.
B. Add a glucuronidable phenolic group to increase phase II
clearance.
C. Substitute a metabolically stable halogen to block
metabolism.
D. Increase lipophilicity to enhance membrane permeation.
Correct answer
B
Rationales
Correct (B): Adding a glucuronidable phenolic group promotes
phase II conjugation (glucuronidation), producing polar
metabolites eliminated more via biliary/renal routes. In CKD,
enhancing conjugation reduces parent-drug exposure and limits
accumulation; careful PK studies are still required to confirm
metabolite clearance.
Incorrect (A): Increasing basicity often enhances tubular
reabsorption and can raise renal retention and accumulation in
CKD.
Incorrect (C): Introducing a metabolically stable halogen
reduces metabolic clearance and increases half-life —
undesirable in renal impairment.
Incorrect (D): Increasing lipophilicity can improve permeability
but generally raises volume of distribution and decreases renal
elimination, risking accumulation.
,Teaching point
Design polar, conjugation-prone groups to favor safe elimination
in renal impairment.
Citation
Brunton, L. L., & Knollmann, B. C. (2023). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics (14th ed.). Ch. 1.
2
Reference
Ch. 1 — Target Identification & Validation
Stem
A biotech company prioritizes targets for a neurodegenerative
disease. Two candidate proteins are identified: Protein X (highly
disease-associated but expressed ubiquitously) and Protein Y
(disease-specific but with low druggability by small molecules).
From a translational risk-benefit perspective, which strategy
best balances efficacy and safety?
A. Prioritize Protein X because ubiquitous expression increases
likelihood of therapeutic effect.
B. Prioritize Protein Y and invest in biologics or modality
engineering despite low small-molecule druggability.
C. Abandon both and target a downstream signaling enzyme to
avoid on-target toxicity.
D. Use a high-throughput screen to find covalent small-
molecule binders to Protein Y.
, Correct answer
B
Rationales
Correct (B): A disease-specific target (Protein Y) lowers on-
target systemic toxicity; investing in alternative modalities
(antibodies, ASOs) is a rational translational choice when small-
molecule druggability is low. This balances efficacy with safety
for chronic neurodegenerative therapy.
Incorrect (A): Ubiquitous expression of Protein X raises high risk
of systemic adverse effects despite strong disease association.
Incorrect (C): Targeting downstream enzymes may dilute
efficacy and miss upstream disease mechanisms; not
necessarily safer without validation.
Incorrect (D): Seeking covalent small molecules for a poorly
druggable target is high risk and may produce irreversible off-
target toxicity.
Teaching point
Favor disease-specific targets; choose modalities that fit target
druggability and safety profile.
Citation
Brunton, L. L., & Knollmann, B. C. (2023). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics (14th ed.). Ch. 1.
3
