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 man with chronic obstructive pulmonary disease
(COPD) is enrolled in a translational study evaluating a semi-
synthetic derivative of a plant alkaloid with promising in vitro
,bronchodilator activity. The lead compound is highly polar and
cleared rapidly in rodent models. Which optimization strategy
most directly addresses low oral bioavailability caused by
excessive polarity while preserving receptor affinity?
A. Add multiple ionizable polar groups to increase water
solubility.
B. Design a lipophilic prodrug that transiently masks polar
groups to improve membrane permeability.
C. Increase molecular weight by adding bulky aromatic rings to
prevent renal clearance.
D. Convert the compound to a permanently charged quaternary
ammonium to enhance receptor binding.
Correct Answer
B
Rationales
Correct (B): A lipophilic prodrug transiently masks polar
functional groups, improving passive membrane permeability
and oral absorption while enzymatic conversion in vivo restores
the active polar pharmacophore; this maintains receptor
affinity. Prodrug approaches are commonly used to resolve
polarity–permeability trade-offs.
A (incorrect): Adding more polar/ionizable groups will worsen
permeability and likely further reduce oral bioavailability
despite increased solubility.
C (incorrect): Increasing molecular weight and aromatic bulk
often reduces permeability and can worsen metabolic liabilities;
,it doesn’t specifically address polarity-driven poor absorption.
D (incorrect): Making a permanently charged quaternary
ammonium increases polarity and prevents crossing lipid
membranes, worsening oral bioavailability.
Teaching Point
Prodrugs can mask polarity to improve permeability while
regenerating the active moiety in vivo.
Citation
Brunton, L. L., & Knollmann, B. C. (2023). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics (14th ed.). Ch. 1.
2
Reference
Ch. 1 — Drug Discovery: From Medicinal Plants to Computer-
Aided Drug Design
Stem
During lead optimization for an oral CNS-active agent, the
medicinal chemistry team raises lipophilicity (logP) to improve
blood–brain barrier penetration. A 55-year-old patient with
mild hepatic impairment is in an early trial. Which consequence
is most likely and should prompt reconsideration of increasing
lipophilicity?
A. Increased hepatic clearance via phase II conjugation.
B. Increased volume of distribution with potential for prolonged
half-life and hepatic accumulation.
, C. Decreased plasma protein binding leading to higher free
fraction and reduced efficacy.
D. Reduced permeability across the blood–brain barrier due to
P-glycoprotein (P-gp) efflux.
Correct Answer
B
Rationales
Correct (B): Increasing lipophilicity typically increases tissue
partitioning and volume of distribution, which can prolong half-
life and result in drug accumulation in patients with impaired
hepatic clearance, raising safety concerns.
A (incorrect): Increased lipophilicity more often decreases
phase II conjugation clearance relative to polar drugs; phase II
generally clears polar metabolites.
C (incorrect): Increased lipophilicity usually increases (not
decreases) plasma protein binding, lowering free fraction.
D (incorrect): While some lipophilic compounds can be P-gp
substrates, increased lipophilicity alone does not predict
reduced BBB permeability via P-gp; P-gp recognition is
structural and not a universal consequence of higher logP.
Teaching Point
Higher lipophilicity → larger Vd and longer half-life; adjust
dosing in hepatic impairment.
Citation
Brunton, L. L., & Knollmann, B. C. (2023). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics (14th ed.). Ch. 1.
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 man with chronic obstructive pulmonary disease
(COPD) is enrolled in a translational study evaluating a semi-
synthetic derivative of a plant alkaloid with promising in vitro
,bronchodilator activity. The lead compound is highly polar and
cleared rapidly in rodent models. Which optimization strategy
most directly addresses low oral bioavailability caused by
excessive polarity while preserving receptor affinity?
A. Add multiple ionizable polar groups to increase water
solubility.
B. Design a lipophilic prodrug that transiently masks polar
groups to improve membrane permeability.
C. Increase molecular weight by adding bulky aromatic rings to
prevent renal clearance.
D. Convert the compound to a permanently charged quaternary
ammonium to enhance receptor binding.
Correct Answer
B
Rationales
Correct (B): A lipophilic prodrug transiently masks polar
functional groups, improving passive membrane permeability
and oral absorption while enzymatic conversion in vivo restores
the active polar pharmacophore; this maintains receptor
affinity. Prodrug approaches are commonly used to resolve
polarity–permeability trade-offs.
A (incorrect): Adding more polar/ionizable groups will worsen
permeability and likely further reduce oral bioavailability
despite increased solubility.
C (incorrect): Increasing molecular weight and aromatic bulk
often reduces permeability and can worsen metabolic liabilities;
,it doesn’t specifically address polarity-driven poor absorption.
D (incorrect): Making a permanently charged quaternary
ammonium increases polarity and prevents crossing lipid
membranes, worsening oral bioavailability.
Teaching Point
Prodrugs can mask polarity to improve permeability while
regenerating the active moiety in vivo.
Citation
Brunton, L. L., & Knollmann, B. C. (2023). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics (14th ed.). Ch. 1.
2
Reference
Ch. 1 — Drug Discovery: From Medicinal Plants to Computer-
Aided Drug Design
Stem
During lead optimization for an oral CNS-active agent, the
medicinal chemistry team raises lipophilicity (logP) to improve
blood–brain barrier penetration. A 55-year-old patient with
mild hepatic impairment is in an early trial. Which consequence
is most likely and should prompt reconsideration of increasing
lipophilicity?
A. Increased hepatic clearance via phase II conjugation.
B. Increased volume of distribution with potential for prolonged
half-life and hepatic accumulation.
, C. Decreased plasma protein binding leading to higher free
fraction and reduced efficacy.
D. Reduced permeability across the blood–brain barrier due to
P-glycoprotein (P-gp) efflux.
Correct Answer
B
Rationales
Correct (B): Increasing lipophilicity typically increases tissue
partitioning and volume of distribution, which can prolong half-
life and result in drug accumulation in patients with impaired
hepatic clearance, raising safety concerns.
A (incorrect): Increased lipophilicity more often decreases
phase II conjugation clearance relative to polar drugs; phase II
generally clears polar metabolites.
C (incorrect): Increased lipophilicity usually increases (not
decreases) plasma protein binding, lowering free fraction.
D (incorrect): While some lipophilic compounds can be P-gp
substrates, increased lipophilicity alone does not predict
reduced BBB permeability via P-gp; P-gp recognition is
structural and not a universal consequence of higher logP.
Teaching Point
Higher lipophilicity → larger Vd and longer half-life; adjust
dosing in hepatic impairment.
Citation
Brunton, L. L., & Knollmann, B. C. (2023). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics (14th ed.). Ch. 1.
