GOODMAN AND GILMAN'S THE
PHARMACOLOGICAL BASIS OF
THERAPEUTICS
14TH EDITION
• AUTHOR(S)LAURENCE BRUNTON;
BJORN KNOLLMANN
TEST BANK
1⃣
Reference
Ch. 1 — Drug Discovery: From Medicinal Plants to Computer-
Aided Drug Design
Stem
A 68-year-old man with chronic hepatitis C and early cirrhosis
volunteers in a phase I trial of a novel ester prodrug discovered
from a medicinal plant extract. The prodrug requires hepatic
carboxylesterase cleavage to release the active acid.
Considering his liver disease, what is the most appropriate
,pharmacologic concern when moving from preclinical to first-in-
human dosing?
Options
A. Increased formation of active metabolite due to upregulated
hepatic esterases in cirrhosis.
B. Reduced conversion to active drug leading to decreased
efficacy and potential accumulation of the prodrug.
C. Enhanced renal excretion of the active metabolite causing
dose-limiting nephrotoxicity.
D. Increased first-pass hepatic clearance resulting in higher
systemic exposure of active drug.
Correct answer
B
Rationale — Correct
Hepatic impairment (cirrhosis) commonly reduces activity of
hepatic enzymes including carboxylesterases; this decreases
activation of ester prodrugs, lowering active drug formation and
potentially causing accumulation of the parent prodrug.
Reduced activation can cause therapeutic failure and
unexpected parent-drug toxicity, requiring dose adjustments or
alternative formulations.
Rationale — Incorrect
A: Cirrhosis does not typically upregulate hepatic esterases;
enzyme activity is usually reduced.
C: Renal excretion is not the primary issue here unless the
active metabolite is renally cleared — the stem indicates
,hepatic activation is rate-limiting.
D: First-pass clearance is decreased, not increased, in cirrhosis;
increased clearance would lower systemic exposure, not raise it.
Teaching Point
Hepatic activation impairment can reduce efficacy and increase
parent-drug accumulation for ester prodrugs.
Citation
Brunton, L. L., & Knollmann, B. C. (2023). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics (14th ed.). Ch. 1.
2️⃣
Reference
Ch. 1 — Drug Discovery: From Medicinal Plants to Computer-
Aided Drug Design
Stem
During lead optimization, a chemist increases a candidate’s
lipophilicity (higher logP) to improve target affinity. A 55-year-
old diabetic patient enrolled in later trials shows higher than
expected volume of distribution and prolonged half-life. Which
discovery-era principle best explains this observation and its
safety consequence?
Options
A. Increased lipophilicity enhances plasma protein binding,
reducing tissue distribution and half-life.
B. Higher lipophilicity tends to increase tissue partitioning (Vd)
, and may increase metabolic clearance, shortening half-life.
C. Increased lipophilicity increases tissue distribution and Vd,
often prolonging half-life and risk of tissue accumulation.
D. Lipophilicity has negligible effects on pharmacokinetics;
observed changes must be assay error.
Correct answer
C
Rationale — Correct
Raising lipophilicity commonly increases a drug’s partitioning
into tissues (larger Vd), which can prolong terminal half-life and
raise the chance of tissue accumulation and off-target toxicity—
especially in chronic dosing. This is a classic lead-optimization
trade-off highlighted in drug discovery.
Rationale — Incorrect
A: Increased plasma protein binding usually reduces free
concentration but does not necessarily reduce tissue
distribution; lipophilicity often increases tissue uptake.
B: Although increased lipophilicity can sometimes increase
metabolic clearance, the net effect often is larger Vd and
prolonged half-life.
D: Lipophilicity is a major determinant of ADME; dismissing it as
negligible is incorrect.
Teaching Point
Higher lipophilicity generally raises Vd and half-life, increasing
accumulation and toxicity risk.
PHARMACOLOGICAL BASIS OF
THERAPEUTICS
14TH EDITION
• AUTHOR(S)LAURENCE BRUNTON;
BJORN KNOLLMANN
TEST BANK
1⃣
Reference
Ch. 1 — Drug Discovery: From Medicinal Plants to Computer-
Aided Drug Design
Stem
A 68-year-old man with chronic hepatitis C and early cirrhosis
volunteers in a phase I trial of a novel ester prodrug discovered
from a medicinal plant extract. The prodrug requires hepatic
carboxylesterase cleavage to release the active acid.
Considering his liver disease, what is the most appropriate
,pharmacologic concern when moving from preclinical to first-in-
human dosing?
Options
A. Increased formation of active metabolite due to upregulated
hepatic esterases in cirrhosis.
B. Reduced conversion to active drug leading to decreased
efficacy and potential accumulation of the prodrug.
C. Enhanced renal excretion of the active metabolite causing
dose-limiting nephrotoxicity.
D. Increased first-pass hepatic clearance resulting in higher
systemic exposure of active drug.
Correct answer
B
Rationale — Correct
Hepatic impairment (cirrhosis) commonly reduces activity of
hepatic enzymes including carboxylesterases; this decreases
activation of ester prodrugs, lowering active drug formation and
potentially causing accumulation of the parent prodrug.
Reduced activation can cause therapeutic failure and
unexpected parent-drug toxicity, requiring dose adjustments or
alternative formulations.
Rationale — Incorrect
A: Cirrhosis does not typically upregulate hepatic esterases;
enzyme activity is usually reduced.
C: Renal excretion is not the primary issue here unless the
active metabolite is renally cleared — the stem indicates
,hepatic activation is rate-limiting.
D: First-pass clearance is decreased, not increased, in cirrhosis;
increased clearance would lower systemic exposure, not raise it.
Teaching Point
Hepatic activation impairment can reduce efficacy and increase
parent-drug accumulation for ester prodrugs.
Citation
Brunton, L. L., & Knollmann, B. C. (2023). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics (14th ed.). Ch. 1.
2️⃣
Reference
Ch. 1 — Drug Discovery: From Medicinal Plants to Computer-
Aided Drug Design
Stem
During lead optimization, a chemist increases a candidate’s
lipophilicity (higher logP) to improve target affinity. A 55-year-
old diabetic patient enrolled in later trials shows higher than
expected volume of distribution and prolonged half-life. Which
discovery-era principle best explains this observation and its
safety consequence?
Options
A. Increased lipophilicity enhances plasma protein binding,
reducing tissue distribution and half-life.
B. Higher lipophilicity tends to increase tissue partitioning (Vd)
, and may increase metabolic clearance, shortening half-life.
C. Increased lipophilicity increases tissue distribution and Vd,
often prolonging half-life and risk of tissue accumulation.
D. Lipophilicity has negligible effects on pharmacokinetics;
observed changes must be assay error.
Correct answer
C
Rationale — Correct
Raising lipophilicity commonly increases a drug’s partitioning
into tissues (larger Vd), which can prolong terminal half-life and
raise the chance of tissue accumulation and off-target toxicity—
especially in chronic dosing. This is a classic lead-optimization
trade-off highlighted in drug discovery.
Rationale — Incorrect
A: Increased plasma protein binding usually reduces free
concentration but does not necessarily reduce tissue
distribution; lipophilicity often increases tissue uptake.
B: Although increased lipophilicity can sometimes increase
metabolic clearance, the net effect often is larger Vd and
prolonged half-life.
D: Lipophilicity is a major determinant of ADME; dismissing it as
negligible is incorrect.
Teaching Point
Higher lipophilicity generally raises Vd and half-life, increasing
accumulation and toxicity risk.
