Direct estimation of the in vivo dissolution of spironolactone, in two particle size ranges, using the single-pass perfusion technique (Loc-I-Gut) in humans.
OBJECTIVE
The objective of this in vivo dissolution study was to investigate the usefulness of the Loc-I-Gut technique for differentiating between the in vivo dissolution rate of two particle sizes of spironolactone, and to compare these in vivo results with corresponding in vitro data.


METHODS
The study included six volunteers, and consisted of three sequential parts (I, II, III). In parts I and III the in vivo dissolution was measured directly by perfusing a semi-open segment in the proximal jejunum. In part II, a solution of spironolactone was administered orally, and the plasma concentration time profile was followed for 48 h. The in vitro dissolution was measured using flow-through cells and different dissolution media simulating human gastrointestinal fluids.


RESULTS
A difference in in vivo dissolution rate of the two different particle sizes was observed, based on perfusion data. This difference was not pronounced in the relative bioavailability of spironolactone administered in two different particle sizes. The relative bioavailability was dependent on the bile acid concentration in vivo. In vitro, dissolution rate of the smaller particles was improved at fasted state bile acid concentrations, while the larger particles were only significantly affected at fed state bile acid concentrations.


CONCLUSIONS
In vivo dissolution studies discriminated between the dissolution rate of the two different particle sizes of spironolactone, based on the perfusate samples. The lack of difference in relative bioavailability, might be explained by the insufficient wash-out of particles after ending the perfusion, reabsorption of surface active ingredients along the GI tract, relatively small difference in particle size and the large inter- and intra-individual differences in pharmacokinetic variables.
Bønløkke
L
L
Department of Pharmaceutics, The Royal Danish School of Pharmacy, Universitetsparken 2, 2100, Copenhagen O, Denmark
Hovgaard
L
L
Kristensen
H G
HG
Knutson
L
L
Lennernäs
H
H
D000327:Adsorption; D000465:Algorithms; D019540:Area Under Curve; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D000451:Mineralocorticoid Receptor Antagonists / Q000737:chemistry / Q000378:metabolism*; D010316:Particle Size; D010477:Perfusion; D012995:Solubility; D013148:Spironolactone / Q000737:chemistry / Q000378:metabolism*
D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone