Profile of P-glycoprotein distribution in the rat and its possible influence on the salbutamol intestinal absorption process.

The intrinsic absorption of salbutamol in different intestinal segments of the rat was measured and related with the corresponding intestinal P-glycoprotein (P-gp) expression levels. The apparent absorption rate constants (k(a), h(-1)) observed in each fraction by means of the "in situ" rat gut absorption method after perfusion of a 0.29-mM isotonic solution of salbutamol were used as absorption indexes. In a separate series of studies, a semiquantitative analysis of the mRNA expression of P-gp by means of polymerase chain reaction and Western blot with an antibody raised against the P-gp were also performed. The "in situ" k(a) values determined in the different segments (h(-1)) showed that the absorption is not homogeneous along the intestinal tract, that is, 0.499 +/- 0.054 for colon, 0.474 +/- 0.052 for the proximal segment, 0.345 +/- 0.014 for the mean, and 0.330 +/- 0.023 for the distal fraction. Addition of verapamil to the perfusion fluid did provide a better absorption of salbutamol in the distal segment. The analysis of the mRNA expression and levels of P-gp showed that the enzyme content in each section of the intestine was inversely related to salbutamol absorption.

Activity-bioavailability balance in oral drug development for a selected group of 6-fluoroquinolones.

A nomogram is proposed to select the best candidate in drug development studies with quinolones and is intended to substitute other possible models. The nomogram is referred to as an activity-bioavailability balance (ABB) because it includes the following two criteria: ABB = [(1/gm MIC drug candidate)/ (1/gm MIC ciprofloxacin)].[(F(calc) drug candidate)/( F(calc) ciproflaxacin)]. The in vitro activity of a group of 4'N-alkyl-ciprofloxacin derivatives was determined together with that of ciprofloxacin, initially against some reference strains and subsequently against 159 clinical isolates of eight selected species. The inverse of the geometric mean of the lowest concentration of drug at which the original inoculum was reduced to no more than two colonies (1/gm MIC), as an antimicrobial activity parameter, and the absolute oral bioavailability index (F(calc)), as predicted from in situ intestinal absorption rate constants, were used for calculation of the ABB values, which ranged from 0.1 to 17 for the species and compounds tested. Ciprofloxacin was the best candidate only against Escherichia coli, whereas 4'N-methyl- and/or 4'N-ethyl-ciprofloxacin showed better or much better ABB values than the model drug, and can be selected as potential drug candidates against the remaining clinical strains. The procedure described could be a useful technique for further drug development studies.