Topic 2-5 Review

Question 1

Perfusion Rate Limitation

Answer 1

• Small lipophilic molecules (many drugs) passing across most membranes
• Very small hydrophilic ones readily passing through pores/channels between cells or some membranes
- Membrane offers no effective barrier to drug molecule, and absorption rate varies with rate of blood flow

Question 2

Membrane Permeability Rate Limitation

Answer 2

• Seen with polar, hydrophilic compounds moving across many membranes
• Poorly permeable, with rate limitation lying with membrane
• Insensitive to changes in blood flow

Question 3

Incomplete Absorption

Answer 3

A. Lack of time
• For dissolution (of sparingly soluble drugs)
• For release (controlled-release products)
• For membrane permeation
B. Competing Reaction
• Instability (gastric pH); substrate for intestinal enzymes or microflora, complexation
C. Hepatic and Gut Wall Extraction
• Low bioavailability occurs for drugs that, when given orally, exhibit a high hepatic extraction ratio or are extensively metabolized in the gut wall. This is called the First-Pass Effect.

Question 4

Enterohepatic Cycling

Answer 4

• For a drug to be highly secreted in the bile, it must be a substrate for the secretory mechanism
• MW greater than 250 g/mole and a polar nature (ionized) are usually requirements (ex: glucuronides)
• Drug goes from liver → bile (stored in GB), GB (emptied by food) → intestine → portal circulation
• If drug is not absorbed in the GI tract, biliary excretion becomes a means of eliminating drug from the body.

Question 5

Window of Therapeutic Concentrations

Answer 5

• Assume that a certain window of plasma concentrations will give the optimal therapeutic response.
• When the concentration is too high, there is a high probability of adverse events.
• When the concentration is too low, there is an unacceptably high probability of a subtherapeutic response.
• The concentrations between the two are referred to as the therapeutic concentration window.

Question 6

Sampling Times

Answer 6

Early exposure, peak time and peak concentration can be properly assessed if the times of sampling are appropriate. Three to 4 samples on the rising part of the curve and 2 to 3 points near the true peak time are needed.

Question 7

Physiochemical Properties of Drug

Answer 7

• Complexation
• Ionization (acid/base)
• Partition coefficient (octanol/water)
• Solubility in water

Question 8

Release Characteristics of Dosage Form

Answer 8

• Disintegration/deaggregation
• Dissolution of drug from granules
- Also dependent on inactive ingredients and formulation variables

Question 9

Physiology of Gastrointestinal Tract

Answer 9

• Colonic retention
• Gastric emptying
• Intestinal motility
• Perfusion of the gastrointestinal tract
• Permeability of gut wall

Question 10

Gastrointestinal Tract Abnormalities and Diseases

Answer 10

• Crohn’s disease
• Diarrhea
• Gastric resection or modification
• Ulcerative colitis

Question 11

PGP and CYP3A

Answer 11

• CYP3A and P-gp share many substrates and inhibitors: together they form a “barrier” to drug absorption
- Net effect is a low oral bioavailability due either to
• efficient back transport of the drug and/or
• metabolism by CYP3A subfamily of enzymes because of the repeated exposure to the enzymes