Loperamide is an opioid agonist used for diarrhea but does not produce central analgesic effects. Which pharmacokinetic property best explains this lack of CNS activity?

• A It undergoes extensive first-pass metabolism in the liver
• B It is highly ionized at physiological pH and cannot cross lipid membranes
• C It is a substrate for P-glycoprotein efflux at the blood-brain barrier ✓
• D It has very low oral bioavailability

Explanation

Loperamide is a P-glycoprotein (MDR1) substrate. P-gp actively pumps it out of the brain capillary endothelial cells back into the blood, preventing significant CNS penetration despite its lipophilicity. This is the pharmacokinetic basis for its peripheral opioid action without central effects. Co-administration with P-gp inhibitors like quinidine can allow CNS penetration and produce respiratory depression.

Reference: Katzung and Trevor's Pharmacology: Examination and Board Review, 13th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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