How does ionization at physiological pH affect drug distribution?

• A. Ionized drugs have reduced membrane permeability, decreasing distribution into lipophilic tissues and across membranes
• B. Ionized drugs have increased membrane permeability, enhancing distribution
• C. Ionization does not affect distribution
• D. Ionized drugs readily cross the blood-brain barrier

Answer: (A)

Ionization at physiological pH changes how easily a drug crosses lipid membranes, which governs distribution. Lipid membranes favor nonpolar, uncharged molecules, so the nonionized fraction of a drug diffuses across membranes and into tissues more readily. The ionized (charged) form is hydrophilic and crosses membranes poorly, limiting its distribution into lipophilic tissues and across barriers like the blood–brain barrier. The balance between ionized and unionized forms depends on the drug’s pKa and the pH of the environment (Henderson–Hasselbalch). Hence, ionized drugs show reduced membrane permeability and, therefore, decreased distribution into lipophilic tissues. The idea that ionized drugs cross membranes more readily or that ionization doesn’t affect distribution or that ionized drugs readily cross the blood-brain barrier is not accurate.