GOODMAN AND GILMAN'S THE
PHARMACOLOGICAL BASIS OF
THERAPEUTICS
14TH EDITION
• AUTHOR(S)LAURENCE BRUNTON;
BJORN KNOLLMANN
TEST BANK
1 — Ch. 1 — Natural Products, Lead Discovery & Prodrugs —
Translational Considerations
Stem: A 72-year woman with reduced hepatic mass from
previous partial hepatectomy is enrolled in a first-in-human trial
of a candidate derived from a medicinal plant. The lead was
advanced as an ester prodrug to improve oral absorption and
relies on hepatic esterase conversion to the active acid. Which
development decision best mitigates risk for this population?
A. Continue with the same prodrug and exclude older adults
from trials.
B. Develop the active acid (non-prodrug) formulation for clinical
,testing in hepatic impairment.
C. Use a higher prodrug dose to compensate for decreased
conversion.
D. Co-administer a nonselective esterase inducer to increase
conversion.
Correct answer: B
Rationale — Correct (B): Converting to the active acid removes
dependence on hepatic activation, lowering variability and
reducing risk in patients with impaired liver function. This is a
translational decision that improves predictability of exposure
without relying on variable hepatic enzyme activity.
Rationale — Incorrect:
A. Excluding older adults avoids the problem but reduces
generalizability and fails to address safety for an important
clinical population.
C. Increasing dose could produce unpredictable parent drug
accumulation or saturable kinetics and worsen toxicity.
D. Pharmacologic induction of esterases is nonselective, unsafe,
and not a viable clinical strategy.
Teaching point: Prodrugs relying on organ-specific activation
increase variability in organ impairment.
Citation: Brunton, L. L., & Knollmann, B. C. (2023). Goodman &
Gilman’s The Pharmacological Basis of Therapeutics (14th ed.).
Ch. 1.
,2 — Ch. 1 — Structure-Based Design & Resistance Mechanisms
Stem: A small-molecule inhibitor targets an essential enzyme in
an infectious organism. Clinical isolates rapidly acquire single
amino-acid substitutions at the orthosteric site that reduce drug
binding. Which rational design strategy most directly reduces
the likelihood of resistance from orthosteric mutations?
A. Increase drug lipophilicity to improve cell penetration.
B. Design a covalent, irreversible inhibitor that targets a non-
mutated active-site nucleophile.
C. Add bulky substituents to bind more tightly to the mutated
orthosteric pocket.
D. Lower molecular weight to improve diffusion and increase
intracellular concentration.
Correct answer: B
Rationale — Correct (B): Designing a covalent inhibitor that
reacts with an invariant nucleophilic residue (if present) can
overcome single residue changes at peripheral binding sites
because covalent bond formation locks the inhibitor in place;
this reduces dependency on high-affinity reversible interactions
that are lost with point mutations.
Rationale — Incorrect:
A. Lipophilicity affects penetration, not resistance arising from
altered binding.
C. Bulky groups may not fit mutated pockets and can worsen
affinity or selectivity.
, D. Lowering MW improves diffusion but does not address
reduced binding affinity due to mutation.
Teaching point: Covalent targeting of invariant residues can
mitigate resistance from orthosteric mutations.
Citation: Brunton & Knollmann (2023). Ch. 1.
3 — Ch. 1 — High-Throughput Screening (HTS) & Hit Triage
Stem: In an HTS campaign you obtain many primary hits.
Several hits are chemically reactive and show activity in the
fluorescence readout but fail in cell-based assays. What is the
best immediate experimental step to triage true leads from
assay-interfering artifacts?
A. Expand screening concentration range for the same
fluorescence assay.
B. Run an orthogonal assay that uses a different detection
principle (e.g., mass spectrometry).
C. Discard all hits that fail the cell assay and continue with the
remaining ones.
D. Prioritize compounds with the lowest molecular weight.
Correct answer: B
Rationale — Correct (B): An orthogonal assay eliminates
detection-method artifacts (e.g., fluorescence quenching, redox
reactivity) and distinguishes genuine target modulation from
assay interference. Mass spectrometry or enzymatic assays with
different readouts confirm mechanism.
PHARMACOLOGICAL BASIS OF
THERAPEUTICS
14TH EDITION
• AUTHOR(S)LAURENCE BRUNTON;
BJORN KNOLLMANN
TEST BANK
1 — Ch. 1 — Natural Products, Lead Discovery & Prodrugs —
Translational Considerations
Stem: A 72-year woman with reduced hepatic mass from
previous partial hepatectomy is enrolled in a first-in-human trial
of a candidate derived from a medicinal plant. The lead was
advanced as an ester prodrug to improve oral absorption and
relies on hepatic esterase conversion to the active acid. Which
development decision best mitigates risk for this population?
A. Continue with the same prodrug and exclude older adults
from trials.
B. Develop the active acid (non-prodrug) formulation for clinical
,testing in hepatic impairment.
C. Use a higher prodrug dose to compensate for decreased
conversion.
D. Co-administer a nonselective esterase inducer to increase
conversion.
Correct answer: B
Rationale — Correct (B): Converting to the active acid removes
dependence on hepatic activation, lowering variability and
reducing risk in patients with impaired liver function. This is a
translational decision that improves predictability of exposure
without relying on variable hepatic enzyme activity.
Rationale — Incorrect:
A. Excluding older adults avoids the problem but reduces
generalizability and fails to address safety for an important
clinical population.
C. Increasing dose could produce unpredictable parent drug
accumulation or saturable kinetics and worsen toxicity.
D. Pharmacologic induction of esterases is nonselective, unsafe,
and not a viable clinical strategy.
Teaching point: Prodrugs relying on organ-specific activation
increase variability in organ impairment.
Citation: Brunton, L. L., & Knollmann, B. C. (2023). Goodman &
Gilman’s The Pharmacological Basis of Therapeutics (14th ed.).
Ch. 1.
,2 — Ch. 1 — Structure-Based Design & Resistance Mechanisms
Stem: A small-molecule inhibitor targets an essential enzyme in
an infectious organism. Clinical isolates rapidly acquire single
amino-acid substitutions at the orthosteric site that reduce drug
binding. Which rational design strategy most directly reduces
the likelihood of resistance from orthosteric mutations?
A. Increase drug lipophilicity to improve cell penetration.
B. Design a covalent, irreversible inhibitor that targets a non-
mutated active-site nucleophile.
C. Add bulky substituents to bind more tightly to the mutated
orthosteric pocket.
D. Lower molecular weight to improve diffusion and increase
intracellular concentration.
Correct answer: B
Rationale — Correct (B): Designing a covalent inhibitor that
reacts with an invariant nucleophilic residue (if present) can
overcome single residue changes at peripheral binding sites
because covalent bond formation locks the inhibitor in place;
this reduces dependency on high-affinity reversible interactions
that are lost with point mutations.
Rationale — Incorrect:
A. Lipophilicity affects penetration, not resistance arising from
altered binding.
C. Bulky groups may not fit mutated pockets and can worsen
affinity or selectivity.
, D. Lowering MW improves diffusion but does not address
reduced binding affinity due to mutation.
Teaching point: Covalent targeting of invariant residues can
mitigate resistance from orthosteric mutations.
Citation: Brunton & Knollmann (2023). Ch. 1.
3 — Ch. 1 — High-Throughput Screening (HTS) & Hit Triage
Stem: In an HTS campaign you obtain many primary hits.
Several hits are chemically reactive and show activity in the
fluorescence readout but fail in cell-based assays. What is the
best immediate experimental step to triage true leads from
assay-interfering artifacts?
A. Expand screening concentration range for the same
fluorescence assay.
B. Run an orthogonal assay that uses a different detection
principle (e.g., mass spectrometry).
C. Discard all hits that fail the cell assay and continue with the
remaining ones.
D. Prioritize compounds with the lowest molecular weight.
Correct answer: B
Rationale — Correct (B): An orthogonal assay eliminates
detection-method artifacts (e.g., fluorescence quenching, redox
reactivity) and distinguishes genuine target modulation from
assay interference. Mass spectrometry or enzymatic assays with
different readouts confirm mechanism.
