Ergot alkaloids: hepatic distribution and estimation of absorption by measurement of total radioactivity in bile and urine.

Abstract

The extent of availability is a measure of the amount of unchanged drug which reaches the systemic circulation following an oral dose. However, absorption as discussed in this communication has the generally accepted meaning of a measure of the disappearance of drug from the gastrointestinal tract and the entrance into the systemic circulation, either as unchanged drug or as metabolite. For many substances, e.g., dihydroergocristine, dihydroergotamine, and ergotamine, excretion in the bile is the most important route of elimination. Determination of the enteral absorption of these compounds from the urinary ratio, i.e., from the ratio of urinary excretion after oral and after intravenous administration, presents a problem, since the quantities found in the wine are small and the hepatic distribution ratio, i.e., the biliary to urinary excretion ratio, can vary depending on the route of administration. We have shown for dihydroergocristine-9,10-3H in the rat that the hepatic distribution ratio calculated from the data for intravenous and oral administration must remain constant if absorption is to be determined from the ratio of oral to intravenous radioactivity excreted either in the bile alone or in the urine alone. If this requirement is not met, but one can account for all of the radioactivity following an oral dose, it is necessary to measure the sum of biliary and urinary excretion of the labeled compounds after oral administration only. This method does not depend on the ratio of the amounts of radioactivity excreted by various routes or on the ratio of unchanged to metabolized compound. By this method, it is possible to detect differences in absorption and in the hepatic distribution ratio. In experiments on bile fistula monkeys, it was shown that the hepatic distribution ratio is, in fact, constant, despite the fact that the enteral absorption of ergotamine is 3 times that of dihydroergotamine.