A group of investigators is currently conducting a phase I clinical trial for a newly developed synthetic opioid that has twice the analgesic capability of morphine. After oral ingestion of a fixed dose by several volunteers, the plasma concentration of the drug is measured and determined to be subtherapeutic. Rectal administration of the same dose of the drug shows a plasma concentration well within the therapeutic range, almost double the level measured after oral intake. Which of the following best accounts for the observed difference in drug concentration following rectal administration when compared to oral administration?

Question

A group of investigators is currently conducting a phase I clinical trial for a newly developed synthetic opioid that has twice the analgesic capability of morphine.  After oral ingestion of a fixed dose by several volunteers, the plasma concentration of the drug is measured and determined to be subtherapeutic.  Rectal administration of the same dose of the drug shows a plasma concentration well within the therapeutic range, almost double the level measured after oral intake.  Which of the following best accounts for the observed difference in drug concentration following rectal administration when compared to oral administration?

Quizplus · Accepted Answer

11ec160b_3c36_376a_9249_a5da49ea828e_MD0001_00 Bioavailability is the fraction of an administered drug that reaches the systemic circulation unchanged. Oral bioavailability is dependent on the intrinsic absorptive properties of the drug as well as any first-pass metabolism that the drug undergoes by enzymes present in the intestine and liver. A drug that exhibits high first-pass metabolism is broken down extensively and will have a low concentration in the systemic circulation (low bioavailability). To efficiently use drugs with high first-pass metabolism, other routes of administration are typically employed (eg, intravenous, sublingual, rectal) to bypass the portal circulation. Rectal drug administration (suppository) allows for partial bypass of first-pass metabolism. Venous drainage of the anorectum above the dentate line is to the portal venous system via the superior rectal veins (drain to inferior mesenteric vein). However, the region below the dentate line drains into the systemic circulation via the middle and inferior rectal veins (drain to internal iliac and internal pudendal veins, respectively). This proportion of venous blood that enters the systemic circulation directly from the rectal region increases the bioavailability of drugs that are otherwise extensively metabolized by the liver following oral administration. (Choice B) Blood flow to different regions of the intestine is directly related to the metabolic activity of the associated mucosa. Greater blood flow rates facilitate absorption and bioavailability of many drugs through the establishment of a favorable concentration gradient. The small intestine has greater blood flow than the colon due to the high rate of active transport required for nutrient digestion and absorption. (Choices C and D) For drugs administered orally, the majority of absorption occurs in the small intestine due to its large surface area. In contrast, the surface area of the rectum is far smaller than that of the small intestine. Therefore, absorption of rectally administered drugs is typically slower and more unpredictable (due to variable amounts of stool) than that of orally administered drugs. This often necessitates more frequent or greater volume dosing to achieve similar blood concentrations in the absence of significant first-pass metabolism. (Choice E) Changes in renal blood flow affect the glomerular filtration rate, which in turn affects the elimination of renally cleared drugs. Patients with impaired renal function have increased bioavailability of substances that are predominantly metabolized by the kidney; these patients may require lower doses to prevent adverse effects. Educational objective: Bioavailability is the fraction of an administered drug that reaches the systemic circulation unchanged. Drugs administered orally enter the portal circulation and are subject to first-pass metabolism. Rectal administration is capable of partially bypassing first-pass metabolism as a proportion of rectal blood flow enters the systemic circulation directly. Drugs that undergo extensive first-pass metabolism have increased bioavailability when administered rectally. __________ References: First-pass elimination. Basic concepts and clinical consequences. (http://www.ncbi.nlm.nih.gov/pubmed/6362950)

A Group of Investigators Is Currently Conducting a Phase I