Arthur R. Mlodozeniec

Disposition of radiolabelled suppositories in humans

The disposition of Witepsol H 15 suppositories radiolabelled with [99m Tc] technetium hydroxymethyldiphosphonate was studied after rectal administration in volunteers. The migration of the radiolabel was monitored continuously by external scintigraphy. The resulting scintiphotos were superimposed on lower GI radiographs to determine the extent of spreading of the dosage form in the rectum. The dosage form migrated approximately 5−7 cm into the rectum in nearly all of the studies and was, in general, confined to the lower and middle regions of the rectum. Since the venous supply to the lower rectum leads primarily to the inferior vena cava, the data presented here indicate that the metabolism of drugs sensitive to the ‘first‐pass’ effect may be partially avoided by their rectal administration.

The effect of pH and concentration on α-methyldopa absorption in man

An open crossover study of the absorption of α‐methyldopa has been conducted in normal healthy adult male volunteers in whom a triple lumen perfusion tube had been placed. Three volunteers were perfused on separate occasions with 0.1 mM α‐methyldopa at pH 4.5, 6.0 and 7.4. Three other volunteers were perfused on separate occasions with 0.1, 1.0 and 10 mM α‐methyldopa at pH 6.0. Two additional subjects were perfused with 0.1 mM α‐methyldopa at pH 6.0. Absorption was not a linear function of concentration above 1 mM α‐methyldopa. There was also a weak trend toward greater absorption near pH 6.0. At higher concentrations of drug in the perfusion solution (10 vs 1 mM), the free fraction of α‐methyldopa in plasma samples was increased significantly. Thus, although absorption of α‐methyldopa is more efficient at lower concentrations, bioavailability may not be substantially enhanced due to increased sulphation in the gut wall. Comparison of permeabilities with previous results from our laboratories suggests the rat is a good model for predicting the behaviour of α‐methyldopa after its oral administration to man.

Drug Distribution and Biliary Excretion Pattern of a Cyclic Somatostatin Analog: A Comparison of 14C Labeled Drug and a 131I lodinated Drug Analog

A cyclic somatostatin analog was compared to an iodinated analog of the same compound with respect to organ distribution and biliary excretion in the rat. The cyclic hexapeptide was radiolabeled with either 14C or 131I (tyrosine). Organ distribution of the iodinated compound as a function of time was nearly identical to that observed for the non-iodinated compound. Results indicated a rapid uptake by the liver and subsequent rapid excretion of the intact peptide in bile. Activity in other organs examined tended to fall off in a manner similar to the activity in blood with sequential samples. Because of the similarity in the in vivo behavior of the two compounds, the iodinated analog was deemed a suitable model for less invasive distribution studies, and was further examined in the dog using external gamma scintigraphy. In the unanesthetized dog the iodine activity was rapidly taken up by liver and collected in the gallbladder, thus exhibiting a similar rapid excretion pattern to that observed in the rat.

Noninvasive Monitoring of the In Vivo Release Characteristics of Rectal Drug Delivery Devices

The rational design of controlled rectal delivery devices suggests that for a given drug there are preferred patterns of controlled release that may optimize the therapeutic value of a drug. The optimized temporal pattern designed within the dosage form should utilize, control or modify the physiological/biochemical environment in which the drug release is occurring.