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 pharmacology lab identifies a natural product that inhibits a
kinase implicated in neuroinflammation but has poor aqueous
solubility and is rapidly metabolized by hepatic CYP3A4. As lead-
optimization begins, which strategy most directly improves oral
bioavailability while preserving the kinase-binding
pharmacophore?
,Options
A. Add a polar sulfonate group to increase water solubility.
B. Design a prodrug that masks a polar group and is cleaved
after absorption.
C. Increase molecular weight to slow hepatic metabolism.
D. Introduce a stereocenter to create an enantiomer with
different potency.
Correct answer
B
Rationales
Correct (B): Prodrugs mask polar or labile functionalities to
enhance membrane permeation and oral absorption; enzymatic
cleavage after absorption can restore the active pharmacophore
while avoiding first-pass metabolism. This directly targets
bioavailability without altering the binding moiety.
Incorrect (A): Increasing polarity via a sulfonate often prevents
membrane permeation and can reduce oral absorption despite
improving solubility.
Incorrect (C): Arbitrarily increasing molecular weight usually
worsens permeability and violates drug-like property guidelines,
often reducing bioavailability.
Incorrect (D): Adding a stereocenter might change potency or
selectivity but does not reliably improve solubility or first-pass
metabolism.
,Teaching point
Prodrugs can enhance absorption while preserving the active
pharmacophore.
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 virtual screening for a CNS target, a candidate
compound scores high for predicted binding but has a
calculated logP of 6 and polar surface area (PSA) of 80 Ų. For
CNS penetration in an elderly patient with reduced P-
glycoprotein function, what is the principal concern about
advancing this candidate?
Options
A. High logP suggests excessive plasma protein binding and
reduced free fraction.
B. PSA of 80 Ų predicts excellent blood–brain barrier
penetration.
C. High lipophilicity increases risk of off-target hepatic toxicity
and poor solubility.
, D. Reduced P-glycoprotein will counteract high logP and ensure
CNS levels are safe.
Correct answer
C
Rationales
Correct (C): A logP of ~6 indicates very high lipophilicity, often
correlating with poor aqueous solubility, metabolic liability,
bioaccumulation, and off-target toxicity—critical risks for CNS
drugs. PSA ~80 Ų is borderline for CNS penetration; high
lipophilicity still raises safety concerns.
Incorrect (A): While high lipophilicity can increase plasma
protein binding, the more immediate translational concern is
solubility and metabolic/toxic liabilities for CNS candidates.
Incorrect (B): PSA ~80 Ų is near the upper limit for CNS
penetration; it does not guarantee excellent BBB crossing.
Incorrect (D): Reduced P-glycoprotein may increase CNS
exposure but does not negate the risks associated with extreme
lipophilicity like toxicity and poor formulation.
Teaching point
Very high lipophilicity often predicts solubility, metabolic and
toxicity liabilities—especially for CNS drugs.
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 pharmacology lab identifies a natural product that inhibits a
kinase implicated in neuroinflammation but has poor aqueous
solubility and is rapidly metabolized by hepatic CYP3A4. As lead-
optimization begins, which strategy most directly improves oral
bioavailability while preserving the kinase-binding
pharmacophore?
,Options
A. Add a polar sulfonate group to increase water solubility.
B. Design a prodrug that masks a polar group and is cleaved
after absorption.
C. Increase molecular weight to slow hepatic metabolism.
D. Introduce a stereocenter to create an enantiomer with
different potency.
Correct answer
B
Rationales
Correct (B): Prodrugs mask polar or labile functionalities to
enhance membrane permeation and oral absorption; enzymatic
cleavage after absorption can restore the active pharmacophore
while avoiding first-pass metabolism. This directly targets
bioavailability without altering the binding moiety.
Incorrect (A): Increasing polarity via a sulfonate often prevents
membrane permeation and can reduce oral absorption despite
improving solubility.
Incorrect (C): Arbitrarily increasing molecular weight usually
worsens permeability and violates drug-like property guidelines,
often reducing bioavailability.
Incorrect (D): Adding a stereocenter might change potency or
selectivity but does not reliably improve solubility or first-pass
metabolism.
,Teaching point
Prodrugs can enhance absorption while preserving the active
pharmacophore.
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 virtual screening for a CNS target, a candidate
compound scores high for predicted binding but has a
calculated logP of 6 and polar surface area (PSA) of 80 Ų. For
CNS penetration in an elderly patient with reduced P-
glycoprotein function, what is the principal concern about
advancing this candidate?
Options
A. High logP suggests excessive plasma protein binding and
reduced free fraction.
B. PSA of 80 Ų predicts excellent blood–brain barrier
penetration.
C. High lipophilicity increases risk of off-target hepatic toxicity
and poor solubility.
, D. Reduced P-glycoprotein will counteract high logP and ensure
CNS levels are safe.
Correct answer
C
Rationales
Correct (C): A logP of ~6 indicates very high lipophilicity, often
correlating with poor aqueous solubility, metabolic liability,
bioaccumulation, and off-target toxicity—critical risks for CNS
drugs. PSA ~80 Ų is borderline for CNS penetration; high
lipophilicity still raises safety concerns.
Incorrect (A): While high lipophilicity can increase plasma
protein binding, the more immediate translational concern is
solubility and metabolic/toxic liabilities for CNS candidates.
Incorrect (B): PSA ~80 Ų is near the upper limit for CNS
penetration; it does not guarantee excellent BBB crossing.
Incorrect (D): Reduced P-glycoprotein may increase CNS
exposure but does not negate the risks associated with extreme
lipophilicity like toxicity and poor formulation.
Teaching point
Very high lipophilicity often predicts solubility, metabolic and
toxicity liabilities—especially for CNS drugs.
Citation
Brunton, L. L., & Knollmann, B. C. (2023). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics (14th ed.). Ch. 1.
