Drug-like properties (2)

Question 1

ABC Transporters

Answer 1

Involved in drug uptake and efflux; key in drug disposition. P-glycoprotein (Pgp) is a major efflux transporter in cancer cells and BBB, contributing to drug resistance.

Question 2

Transporters in Renal Epithelial Cells

Answer 2

Facilitate secretion and reabsorption. Key examples: Organic Cation Transporters (OCT1, OCT2), Multidrug Resistance Proteins (MRP2, MRP4), P-glycoprotein (Pgp).

Question 3

P-glycoprotein (Pgp)

Answer 3

Efflux pump in multiple tissues; protects against xenobiotics. Important in drug resistance, elimination in liver/kidney.

Question 4

MDR Ratio

Answer 4

Ratio indicating efflux by Pgp. Should be <10 to avoid high efflux. Ispinesib (Eg5 inhibitor) has MDR ratio ~9.5.

Question 5

hERG Channel

Answer 5

Voltage-gated K+ channel crucial for cardiac repolarization. Blockage can cause fatal arrhythmias (Torsade de Pointes).

Question 6

hERG Inhibition Structural Features

Answer 6

Basic amine (pKa > 7.3), lipophilic substructures (ClogP > 3.7), absence of negatively ionizable groups.

Question 7

hERG Risk Mitigation

Answer 7

Lower amine pKa, add H-bond acceptors/acidic groups, reduce lipophilicity.

Question 8

hERG Inhibition Classification

Answer 8

IC50 < 0.1 µM (highly potent); IC50 > 10 µM (weak/no inhibition).

Question 9

Metabolic Stability

Answer 9

Drug clearance via enzymatic metabolism, mainly in the liver. Involves Phase I (oxidation, reduction) and Phase II (conjugation) reactions.

Question 10

Phase I Metabolism

Answer 10

Reactions: aliphatic/aromatic oxidation (CYP), alcohol/aldehyde oxidation (dehydrogenases).

Question 11

Phase II Metabolism

Answer 11

Reactions: glucuronidation (UDP-GT), sulfation (Sulfotransferase), increasing drug hydrophilicity.

Question 12

Microsomal Stability

Answer 12

Uses liver microsomes and NADPH to determine hepatic clearance. Low clearance: CLint < 8.6 (human).

Question 13

Hepatocyte Stability

Answer 13

Accounts for both Phase I & II metabolism. Low clearance: CLint < 3.5 (human).

Question 14

Barriers in Bloodstream

Answer 14

Plasma enzyme hydrolysis (aldolase, lipase), plasma protein binding (albumin, α1-acid glycoprotein), RBC binding.

Question 15

Plasma Protein Binding (PPB)

Answer 15

Determines free (active) drug fraction. Measured via equilibrium dialysis. Fu < 0.1 means extensive binding (>90% bound).

Question 16

CYP Enzymes

Answer 16

Major drug-metabolizing enzymes (e.g., CYP3A4, CYP2D6). Inhibition can lead to increased plasma drug levels and toxicity.

Question 17

CYP Inhibition Assay

Answer 17

Incubation with HLM and specific substrates, monitored by LC-MS/MS. IC50 calculated.

Question 18

CYP Inhibition Classification

Answer 18

IC50 < 1 µM (potent), IC50 > 10 µM (weak/no inhibition).

Question 19

Pharmacokinetics (PK)

Answer 19

Study of drug absorption, distribution, metabolism, and excretion (ADME).

Question 20

Absorption

Answer 20

Key metrics: Cmax (peak plasma concentration), Tmax (time to peak).

Question 21

Distribution

Answer 21

Volume of distribution (Vd = Dose/C0).

Question 22

Clearance

Answer 22

Total body clearance (Cl = Dose/AUC).

Question 23

Elimination

Answer 23

Half-life (t1/2 = 0.693/k).

Question 24

Bioavailability

Answer 24

Ratio of oral to IV drug exposure. Higher bioavailability indicates better absorption.

Question 25

Key Drug Development Assays

Answer 25

Transporter interaction (Pgp, MDR ratio), metabolic stability (microsomes, hepatocytes), PPB, CYP inhibition, hERG inhibition.

Question 26

Optimization Strategies

Answer 26

Structural modifications to improve safety, metabolism, and bioavailability. Early screening for metabolic liabilities.