A volunteer receives a single oral dose of a drug. The plasma concentration-time profile shows an initial peak, followed by a decline, and then a distinct second smaller peak at 6 hours before final elimination. The most likely explanation for this secondary peak is:

• A Flip-flop kinetics due to slow absorption
• B Saturable first-pass metabolism releasing stored drug from the liver
• C A genetic polymorphism causing biphasic metabolism
• D Enterohepatic recirculation of the drug via bile and intestinal deconjugation ✓

Explanation

Enterohepatic cycling produces a characteristic double-peak profile: drug or its conjugates are secreted into bile, delivered to the intestine, hydrolysed by gut flora or intestinal enzymes, and reabsorbed, creating a second rise in plasma concentration. Drugs such as chloramphenicol, digoxin and morphine glucuronide show this pattern. Flip-flop kinetics prolongs the absorption phase but does not create a discrete second peak, and neither polymorphic metabolism nor saturable first-pass metabolism produces this morphology.

Reference: Katzung's Basic and Clinical Pharmacology, 15th ed.

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