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

An open crossover study of the absorption of alpha-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 alpha-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 alpha-methyldopa at pH 6.0. Two additional subjects were perfused with 0.1 mM alpha-methyldopa at pH 6.0. Absorption was not a linear function of concentration above 1 mM alpha-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 alpha-methyldopa in plasma samples was increased significantly. Thus, although absorption of alpha-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 alpha-methyldopa after its oral administration to man.

Disposition of radiolabelled suppositories in humans.

The disposition of Witepsol H 15 suppositories radiolabelled with [99mTc] 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.

Drug Distribution and Biliary Excretion Pattern of a Cyclic Somatostatin Analog: A Comparison of (14)C Labeled Drug and a (131)I 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 (14)C or (131)I (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.

Mechanism of surface lubrication: influence of duration of lubricant-excipient mixing on processing characteristics of powders and properties of compressed tablets.

A mathematical expression for tablet hardness was related to lubricant mixing by considering increases in the surface coverage with prolonged mixing time. The duration of lubricant mixing significantly changed the apparent bulk volume of the mix, ejection force during tableting, hardness, and disintegration and dissolution properties of tablets. These findings may provide some rationale for the changes in processing characteristics and properties of finished drug products often encountered in the scale-up of solid dosage formulations. Several lubrication mechanisms are discussed in connection with the duration of mixing effects and scanning microscopy studies.