A group of investigators is conducting a phase I clinical trial for a newly developed synthetic opioid. After several volunteers ingest a fixed oral dose, the plasma concentrations of the active drug and its inactive metabolites are measured. The plasma concentration of the drug is determined to be subtherapeutic. After rectal administration of the same dose of the drug, the peak drug plasma concentration is almost double the level measured after oral administration. Which of the following best accounts for the observed difference in the concentration of the active drug?
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Bioavailability is the fraction of an administered drug that reaches the systemic circulation unchanged. Oral bioavailability depends on the drug's intrinsic ability to be absorbed by the gastrointestinal mucosa (eg, poor with vancomycin) and its propensity for metabolization by intestinal and hepatic enzymes (first-pass metabolism).
When a drug has high first-pass metabolism, large amounts of its metabolites (rather than the drug itself) enter the systemic circulation. Drugs that are largely inactivated by first-pass metabolism (ie, low oral bioavailability) are often administered by a route that bypasses the portal circulation (eg, intravenous, sublingual).
Rectal administration (via suppository) allows a drug to partially escape first-pass metabolism. Venous drainage of the anorectum above the dentate line is to the portal venous system via the superior rectal veins (which drain to the inferior mesenteric vein). However, the region below the dentate line drains into the systemic circulation via the middle and inferior rectal veins (which drain to the internal iliac and internal pudendal veins, respectively). For a drug that is inactivated by first-pass metabolism, the rectal route allows a higher proportion of the drug to bypass portal circulation, increasing bioavailability.
(Choices B, C, and D) For orally administered drugs, the small intestine is a major site of absorption owing to its large surface area and high blood flow rates. In contrast, the rectum has a much smaller surface area, lower blood flow rates, and often contains absorptive stool. Therefore, rectally administered drugs are typically absorbed more slowly and erratically compared to orally administered drugs.
(Choice E) Reduced renal blood flow causes a decrease in the glomerular filtration rate (GFR), which in turn slows elimination of renally excreted drugs (ie, increases bioavailability). Patients with reduced GFR may require a lower dose to prevent adverse effects. However, the route of administration does not impact drug clearance.
Educational objective:
Drugs administered orally must pass through the portal circulation and are subject to first-pass metabolism by intestinal and hepatic enzymes. Rectal administration is capable of partially bypassing first-pass metabolism due to the portion of venous outflow that goes directly to the systemic circulation; drugs with extensive first-pass metabolism have increased bioavailability when administered rectally.