Bioavailability And First-Pass Clearance

Front 1

Absorption

Back 1

The extent to which intact drug is absorbed from the gut lumen into the portal circulation. This is expressed as the faction of the dose which is absorbed from the gut.

Front 2

First pass clearance

Back 2

the extent to which a drug is removed by the liver during its first passage in the portal blood through the liver to the systemic circulation.

Front 3

Bioavailability

Back 3

the fraction of the dose which reaches the systemic circulation as intact drug. This is expressed as F.

Front 4

F = fg * fh

Back 4

Bioavailability = the fraction absorbed * fraction escaping first-pass clearance

Front 5

Determinants of drug absorption from the gut

Back 5

Dissolution

Gastric emptying rate

Intestinal motility

Drug interactions in the gut lumen

Passage through the gut wall

Front 6

Dissolution

Back 6

physico-chemical properties of drug (including solubility and molecular charge.

Crystal size and form.

excipients.

special dosage forms (sustained release, enteric coated).

ph of stomach and small intestine.

Front 7

Gastric emptying rate

Back 7

stability of drug at acid pH.

solution or solid dosage forms (liquids and small particles empty more quickly).

affected by food, antacids, drugs (opiates, anticholinergics, metoclopramide), disease (autonomic neuropathy)

Front 8

Intestinal motility

Back 8

dissolution of slowly soluble drugs (digoxin, sustained release formulations).

Chemical degradation or metabolism by microflora.

Front 9

Drug interactions in the gut lumen

Back 9

complexation (tetracyclines with divalent metal ions).

adsorption (anion exchange resins).

food interactions (many antibiotics).

Front 10

Passage through the gut wall

Back 10

Physico-chemical characteristics of the drug (quaternary ammonium compounds).

Metabolism by enzymes in the intestinal endothelium.

Transport by drug exporter proteins (e.g. p-glycoprotein).

Front 11

What is p-glycoprotein?

Back 11

important protein of the cell membrane that pumps many foreign substances out of cells. More formally, it is an ATP-dependent efflux pump with broad substratespecificity.

Front 12

Bioequivalence

Back 12

two formulations of a drug.

the extents and rates of absorption of drug from them are so similar that there is likely to be no clinically important difference between their effects, either therapeutic or adverse.

Front 13

AUC

Back 13

The area under the curve is the area under the curve (mathematically known as integral) in a plot of concentration of drug in blood plasma against time. Typically, the area is computed starting at the time the drug is administered and ending when the concentration in plasma is negligible. In practice, the drug concentration is measured at certain discrete points in time and the trapezoidal rule is used to estimate AUC.

Front 14

What is absolute bioavailability measured against?

Back 14

an intravenous reference dose (the bioavailability of an intravenous dose is 100% by definition).

Front 15

How is the bioavailability of the oral formulation calculated?

Back 15

give a group of volunteers intravenous and oral doses of the drug on separate occasions.

The areas under the plasma drug conc versus time curves, after the two doses are compared.

Front 16

how is relative bioavailability measured?

Back 16

when one oral formulation (test formulation) is measured against a second oral (reference formulation). ratios of auc should be between 0.8 to 1.25

Front 17

Name a low hepatic extraction ratio drug?

Back 17

Theophylline is poorly extracted by the liver and nearly all the dose gets through the liver first pass and bioavailability is essentially complete as long s they are well absorbed from the gut.

Front 18

Name a high hepatic extraction ratio drug

Back 18

verapamiil is efficiently extracted by the liver most is extracted during first pass so only a little reaches systemic circulation.

Front 19

What is normal liver blood flow?

Back 19

Around 90 L/hour

Front 20

Why is first pass clearance important?

Back 20

Variability in drug response.

Relationship between oral and intravenous doses.

Alternative routes of administration.

Drug interactions.

Liver disease.

Front 21

What is glyceryl trinitrate and how is it administered and why?

Back 21

Used to treat angina and heart failure.

Highly extracted by liver so administered sub-lingually to by-pass the liver.

Sub lingual route because venous drainage from mouth goes straight to the systemic circulation and bypasses first-pass clearance.

Front 22

What fraction of the rectal circulation is systemic rather than portal

Back 22

about one third, so this rectal administration reduces first pass clearance

Front 23

What is Bioavailability?

Back 23

The fraction of the dose reaching the systemic circulation intact.

A measure of both first-pass metabolism and absorption from the gut.

Front 24

What is the bioavailability given the following information:-

hepatic extraction ratio of 0.6 and 40% absorbed from the gut?

Back 24

0.4 * 0.4 = 1.6