GOODMAN AND GILMAN'S THE
PHARMACOLOGICAL BASIS OF
THERAPEUTICS
14TH EDITION
• AUTHOR(S)LAURENCE BRUNTON;
BJORN KNOLLMANN
TEST BANK
1⃣
Reference
Ch. 1 — Natural-product leads & ethnopharmacology
Stem
A 62-year-old patient with metastatic prostate cancer enrolls in
a phase I study testing a new anticancer agent derived from a
tropical plant traditionally used for inflammation. Preclinical
data show potent antiproliferative effects but also CYP3A4-
mediated metabolism. As a translational pharmacologist, you
must assess risks before first-in-human dosing. Which
,preclinical finding most strongly increases concern for an
unexpectedly high variability in human exposure and drug–drug
interactions?
A. The plant alkaloid shows an IC₅₀ in tumor cell lines at low
nanomolar concentrations.
B. In human liver microsomes the compound is converted
rapidly to a single major metabolite via CYP3A4.
C. The compound shows low aqueous solubility but high
permeability in Caco-2 cells.
D. The molecule is a P-glycoprotein substrate in in vitro
transport assays.
Correct answer
B
Rationale — Correct (B)
Rapid CYP3A4-mediated metabolism predicts that
coadministration with strong CYP3A4 inhibitors or inducers will
substantially alter systemic exposure; CYP3A4 polymorphisms
and concomitant medications common in older cancer patients
increase variability and interaction risk. Clinically this requires
thorough DDI evaluation and careful starting dose selection for
first-in-human trials.
Rationales — Incorrect
A. Potent in vitro activity (low IC₅₀) supports efficacy potential
but doesn’t predict human PK variability or DDIs.
C. Low solubility with high permeability suggests a BCS class II
drug — formulation and bioavailability issues, but not direct
,DDI variability.
D. P-glycoprotein substrate status affects distribution and CNS
penetration and can cause variability, but CYP3A4 metabolism is
a larger driver of systemic DDIs.
Teaching point
CYP-mediated clearance, especially via CYP3A4, is a primary
source of human exposure variability and drug–drug
interactions.
Citation
Brunton, L. L., & Knollmann, B. C. (2023). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics (14th ed.). Ch. 1.
2️⃣
Reference
Ch. 1 — Phenotypic vs target-based screening
Stem
A biotech company screens a 200,000-compound library against
cultured neurons to find neuroprotective agents (phenotypic
screen). An alternative team proposes target-based screening
against a specific kinase implicated in neuronal death. For
translational success in a complex CNS disease with unclear
pathophysiology, which rationale most strongly favors
phenotypic screening?
A. Phenotypic screens are faster and require no cellular assays.
B. Phenotypic screens detect compounds with desirable whole-
, cell effects regardless of unknown targets.
C. Target-based screening always yields more selective
compounds.
D. Phenotypic screening eliminates the need for subsequent
mechanism-of-action studies.
Correct answer
B
Rationale — Correct (B)
Phenotypic screening captures functional outcomes in intact
cells or tissues, identifying compounds that produce beneficial
phenotypes even when the precise molecular target is unknown
— particularly valuable for complex CNS diseases where target
validity is uncertain.
Rationales — Incorrect
A. Phenotypic screens use cellular/organismal assays and are
not inherently faster; they can be resource-intensive.
C. Target-based approaches can produce selective ligands for a
known target but may fail if the target is not causally related to
disease phenotype.
D. Phenotypic hits still require mechanism-of-action studies for
development and regulatory acceptance.
Teaching point
Phenotypic screens can identify therapeutically relevant
molecules when target biology is uncertain.
PHARMACOLOGICAL BASIS OF
THERAPEUTICS
14TH EDITION
• AUTHOR(S)LAURENCE BRUNTON;
BJORN KNOLLMANN
TEST BANK
1⃣
Reference
Ch. 1 — Natural-product leads & ethnopharmacology
Stem
A 62-year-old patient with metastatic prostate cancer enrolls in
a phase I study testing a new anticancer agent derived from a
tropical plant traditionally used for inflammation. Preclinical
data show potent antiproliferative effects but also CYP3A4-
mediated metabolism. As a translational pharmacologist, you
must assess risks before first-in-human dosing. Which
,preclinical finding most strongly increases concern for an
unexpectedly high variability in human exposure and drug–drug
interactions?
A. The plant alkaloid shows an IC₅₀ in tumor cell lines at low
nanomolar concentrations.
B. In human liver microsomes the compound is converted
rapidly to a single major metabolite via CYP3A4.
C. The compound shows low aqueous solubility but high
permeability in Caco-2 cells.
D. The molecule is a P-glycoprotein substrate in in vitro
transport assays.
Correct answer
B
Rationale — Correct (B)
Rapid CYP3A4-mediated metabolism predicts that
coadministration with strong CYP3A4 inhibitors or inducers will
substantially alter systemic exposure; CYP3A4 polymorphisms
and concomitant medications common in older cancer patients
increase variability and interaction risk. Clinically this requires
thorough DDI evaluation and careful starting dose selection for
first-in-human trials.
Rationales — Incorrect
A. Potent in vitro activity (low IC₅₀) supports efficacy potential
but doesn’t predict human PK variability or DDIs.
C. Low solubility with high permeability suggests a BCS class II
drug — formulation and bioavailability issues, but not direct
,DDI variability.
D. P-glycoprotein substrate status affects distribution and CNS
penetration and can cause variability, but CYP3A4 metabolism is
a larger driver of systemic DDIs.
Teaching point
CYP-mediated clearance, especially via CYP3A4, is a primary
source of human exposure variability and drug–drug
interactions.
Citation
Brunton, L. L., & Knollmann, B. C. (2023). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics (14th ed.). Ch. 1.
2️⃣
Reference
Ch. 1 — Phenotypic vs target-based screening
Stem
A biotech company screens a 200,000-compound library against
cultured neurons to find neuroprotective agents (phenotypic
screen). An alternative team proposes target-based screening
against a specific kinase implicated in neuronal death. For
translational success in a complex CNS disease with unclear
pathophysiology, which rationale most strongly favors
phenotypic screening?
A. Phenotypic screens are faster and require no cellular assays.
B. Phenotypic screens detect compounds with desirable whole-
, cell effects regardless of unknown targets.
C. Target-based screening always yields more selective
compounds.
D. Phenotypic screening eliminates the need for subsequent
mechanism-of-action studies.
Correct answer
B
Rationale — Correct (B)
Phenotypic screening captures functional outcomes in intact
cells or tissues, identifying compounds that produce beneficial
phenotypes even when the precise molecular target is unknown
— particularly valuable for complex CNS diseases where target
validity is uncertain.
Rationales — Incorrect
A. Phenotypic screens use cellular/organismal assays and are
not inherently faster; they can be resource-intensive.
C. Target-based approaches can produce selective ligands for a
known target but may fail if the target is not causally related to
disease phenotype.
D. Phenotypic hits still require mechanism-of-action studies for
development and regulatory acceptance.
Teaching point
Phenotypic screens can identify therapeutically relevant
molecules when target biology is uncertain.
