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Biomedical subjects

J M Plá-Delfina

Publications and source records attributed to J M Plá-Delfina.

At least 19 recordsLinked to original sources
PubMed2000

Intrinsic absolute bioavailability prediction in rats based on in situ absorption rate constants and/or in vitro partition coefficients: 6-fluoroquinolones.

A preliminary study attempting to predict the intrinsic absolute bioavailability of a group of antibacterial 6-fluoroquinolones-including true and imperfect homologues as well as heterologues-was carried out. The intrinsic absolute bioavailability of the test compounds, F, was assessed on permanently cannulated conscious rats by comparing the trapezoidal normalized areas under the plasma concentration-time curves obtained by intravenous and oral routes (n = 8-12). The high-performance liquid chromatography analytical methods used for plasma samples are described. Prediction of the absolute bioavailability of the compounds was based on their intrinsic rat gut in situ absorption rate constant, k(a). The working equation was: where T represents the mean absorbing time. A T value of 0.93 (+/-0.06) h provides the best correlation between predicted and experimentally obtained bioavailabilities (F' and F, respectively) when k(a) values are used (slope a = 1.10; intercept b = -0.05; r = 0.991). The k(a) values can also be expressed in function of the in vitro partition coefficients, P, between n-octanol and a phosphate buffer. In this case, theoretical k(a) values can be determined with the parameters of a standard k(a)/P correlation previously established for a group of model compounds. When P values are taken instead of k(a) values, reliable bioavailability predictions can also be made. These and other relevant features of the method are discussed.

Absorption↗
PubMed1995

Biophysical models as an approach to study passive absorption in drug development: 6-fluoroquinolones.

A preliminary study attempting to assess and explain the intestinal absorption of a series of antibacterial 7-piperazinyl-6-fluoroquinolones is presented. The synthesis, n-octanol partition coefficients, intrinsic rat gut in situ absorption rate constants, and in vitro antibacterial activity data found for these homologous compounds are described. A fluorimetric, reverse-phase HPLC method was performed for the quantification of the quinolones in absorption and partition samples. Equations based on two classic biophysical absorption models are given for predicting the intrinsic absorption features of the series according to the partition data or merely single structural parameters. In situ absorption rate constants were found to increase by a factor of 9.7-13.5 for moderately lipophilic derivatives relative to the simplest compound, while antibacterial activity decreased only by a factor of 4. In vivo absorption tests with two representative members of the series were carried out and the results showed a good accordance with those found in situ. This makes these compounds or related ones with similar partition features excellent candidates for further pharmacokinetic and pharmacological testing. The study can serve as an example of how to prevent potential absorption problems associated with the development of new drugs.

Administration, Oral↗
PubMed1994

Intestinal absorption pathway of gamma-aminobutyric acid in rat small intestine.

Intestinal absorption of gamma-aminobutyric acid (GABA), as a model compound for gamma-aminoacids, has not been extensively studied from the kinetic viewpoint. Since data from our laboratory suggested that some competition arises between intestinal absorption of beta-alanine and GABA and since our intent was to maintain the aqueous stagnant diffusion layer in order to approach absorption tests to in vivo physiological conditions, a rat jejunum in situ study was undertaken in order to gain an insight into the mechanism of GABA absorption. In the present paper, results from assays using isotonic perfusion solutions with starting GABA concentrations ranging from 1 to 50 mM are reported. They show that the intestinal absorption of the gamma-aminoacid can be apparently described as a specialized transport mechanism which obeys Michaelis-Menten and first-order kinetics. Parameter values found were Vm = 13.99 +/- 2.37 mM h-1, Km = 3.87 +/- 0.63 mM, and ka(passive) = 0.362 +/- 0.120 h-1. Through the perfusion of 5 mM beta-alanine solutions containing variable concentrations of GABA (from 5 to 50 mM), a partially competitive inhibition of beta-alanine absorption was apparently characterized.

Alanine↗
PubMed1994

Influence of gamma-aminobutyric acid on baclofen intestinal absorption.

Since previous studies suggested that baclofen absorption in the rat middle intestine was inhibited by beta-alanine and therefore mediated, at least in part, by the beta-aminoacid carrier, we focused our new studies on the analysis of the possible inhibition of the drug by a gamma-aminoacid model compound, gamma-aminobutyric acid (GABA). A rat jejunum in situ study was undertaken in order to evaluate the effect of GABA on baclofen absorption and to establish the inhibition model. Assays using isotonic perfusion solutions of 0.5 mM baclofen with starting GABA concentrations ranging from 0 to 100 mM are reported. The results show that the absorption rate pseudoconstants of the drug decrease at the GABA concentration increases, with a limiting value of 0.65 h-1 (+/- 0.01). A partial competitive inhibition or complete competitive inhibition in the presence of a passive component could define the interaction phenomena between the two substances. Kinetic absorption parameters for GABA in the presence and absence of baclofen (Ki = 5.67 +/- 1.54, Km = 3.87 +/- 0.63) suggest the existence of more than one intestinal carrier system for baclofen or GABA.

Animals↗
PubMed1993

Permeation mechanisms through artificial lipoidal membranes and effects of synthetic surfactants on xenobiotic permeability.

Through the use of permeation/lipophilicity correlations, the mechanisms of permeation of selected test compounds across artificial lipoidal membranes of the polysiloxane type, in the absence and in the presence of a nonionic surfactant (Polysorbate 80), are investigated, in order to design "in vitro" conditions and features suitable for reproducing "in vivo" intestinal absorption tests, as well as to validate some conclusions arising from "in situ" rat gut experiments about the effects of the synthetic surfactants on drug and xenobiotic absorption processes. Six 4-alkylanilines showing a perfect homology were used as test compounds. The reported results clearly show that the in situ biophysical absorption (diffusion) models are completely reproduced by in vitro tests, provided that perfect sink conditions are achieved. Further selection of artificial membrane polarity should be necessary, however, in order to exactly equalize in vitro and in situ permeation rates. As far as the synthetic surfactant action on permeability is concerned, our conclusions are similar to those drawn from in situ studies, except that the effect of the surfactant on membrane polarity is much smaller and the micelle-solubilizing effect somewhat larger. The disruption of the aqueous stagnant diffusion layers adjacent to the membranes by the surfactant has been conclusively demonstrated. A clear first-element deviation for aniline, which prevents its inclusion as a term of the tested series, has been observed; this feature should be borne in mind whenever any in vivo/in vitro correlation has to be established.

Absorption↗
PubMed1992

Nonlinearities in amoxycillin pharmacokinetics. I. Disposition studies in the rat.

Several features of amoxycillin pharmacokinetics in man are not well known in spite of the extensive clinical use of the antibiotic. In this paper it is demonstrated that amoxycillin disposition kinetics in rats is clearly nonlinear, and that this may be due mainly to its elimination mechanisms. At different intravenous bolus dose levels, and in steady-state perfusion studies, the most striking feature is an increased renal clearance as dose increases (from 3.5 to 7.0 mg kg-1 for intravenous bolus, and from 4.6 to 20.0 micrograms min-1 for intravenous perfusions). This phenomenon has been attributed to a saturation of the active renal tubular reabsorption of the antibiotic. When the intravenous dose is substantially increased (28.0 mg kg-1 bolus), plasma clearance tends to stabilize, probably because saturation of the active tubular secretion of amoxycillin takes place at these doses. Extrarenal clearance seems to remain linear throughout the entire dose range. On the basis of these observations and a review of selected bibliography, an interpretation of the kinetic disposition behaviour of amoxycillin in man is attempted.

Amoxicillin↗
PubMed1992

Nonlinearities in amoxycillin pharmacokinetics. II. Absorption studies in the rat.

Most factors influencing amoxycillin oral absorption are, even today, unknown. Since many dosage schedules have been shown to lead to incomplete absorption, it would be desirable to find a suitable animal model where these factors could be studied in depth. In this paper, it is shown that, in the rat, plasma level curves obtained after oral doses of 7 and 28 mg kg-1 are poorly fitted using first-order absorption kinetics and that the best fit is obtained through the use of an input equation combining zero and first-order kinetics. In contrast, plasma level curves found after intraduodenal administration of amoxycillin solutions (7 mg kg-1) are well fitted by first-order input kinetics. It would seem that precipitation of some dose fraction of the orally administered antibiotic may occur in proximal gastrointestinal areas; this plays an important role in absorption profiles and prevents any possible saturation phenomena associated with active intestinal transport of the antibiotic. A comparative study of available human oral data revealed close similarities with those found in rats. As a result, the plasma level curve fitting was greatly improved by the use of the input function described here for the rat. Although oral bioavailability (as assessed from urinary excretion data) is lower in this latter species, the use of suitable correction factors led to superimposable plasma level curves in the two species, as occurred in previously reported disposition studies.

Amoxicillin↗
PubMed1991

Partially competitive inhibition of intestinal baclofen absorption by beta-alanine, a nonessential dietary aminoacid.

In situ intestinal absorption of baclofen in the rat in the presence of beta-alanine has been investigated. Through the perfusion of 0.50 mM baclofen solutions containing variable concentrations of the aminoacid (from 5 to 100 mM), a partially competitive inhibition of baclofen absorption was characterized: absorption rate pseudoconstants of the spasmolytic drug decrease as beta-alanine concentration increases, until a limiting value is obtained (36.8 per cent of that found for baclofen alone). A computer method was developed in order to calculate parameters governing baclofen absorption in the presence of beta-aminoacid, with the following results: Vm = 11.22 mM h-1; Km = 7.42 mM; Ki = 2.45 mM; alpha = 2.78; r = 0.998. Kinetic absorption parameters for beta-alanine in the presence of 0.50 mM baclofen were also assessed: Vm = 49.88 mM h-1; Km = 12.16 mM; r = 0.998, which, as can be expected, do not significantly differ from those previously found in the absence of the spasmolytic. It is concluded that baclofen and beta-alanine compete for the same intestinal carrier system, although the values of the interaction parameters, particularly Ki, can be more or less biased due to the limitations of the procedure and/or to the existence of some other carrier system for absorption. Possible practical implications of this phenomenon are briefly discussed.

Animals↗
PubMed1991

Intestinal absorption kinetics of a series of aminopenicillins and azidocillin. A comparative study in the rat.

Intestinal absorption rate constants of amoxicillin, ampicillin, epicillin, cyclacillin and azidocillin, by means of a static in situ intestinal perfusion method has been estimated. Luminal remaining antibiotic concentrations were determined using a standard microbiological technique. In order to establish statistically better absorption kinetics, five dose levels were used, ranging from 10 to 1000 micrograms/ml, and first order, Michaelis-Menten and combined first-order and Michaelis-Menten differential model equations were fitted to experimental data found for each antibiotic. According to the AIC test, the best equation for absorption kinetics was selected. Amoxicillin and ampicillin absorption mechanisms were better described by combined kinetics, while for cyclacillin and epicillin the most probable kinetics was that of Michaelis-Menten. For azidocillin, the only non-aminopenicillin component of this series, first order kinetics should be statistically selected.

Amoxicillin↗
PubMed1990

Kinetics of the intestinal uptake of zinc acexamate in normal and zinc-depleted rats.

The uptake of zinc as acexamic acid salt in the small intestine of the anaesthetized rat was shown to be a two-phase process in normal animals. The first phase is rapid mucosal binding which satisfies the Freundlich isotherm equation and which involves about 30 per cent of the initially perfused zinc. The second phase was characterized as an apparent absorption step which obeys Michaelis-Menten and first-order combined kinetics, with the following parameters: Vm = 6.51 mg h-1; Km = 2.96 mg; ka = 0.306 h-1. In largely non-saturated conditions, an apparent global rate constant of about 2.50 h-1 was calculated. No significant interference due to endogenous zinc excretion into the small intestine was observed during the absorption period. In zinc-deficient animals, the two phases were not so well characterized. Binding was non-linear and apparent absorption efficiency was much greater at high zinc concentrations, so no evidence of saturable kinetics was found, thus confirming the hypothesis of a homeostatic zinc regulation mechanism.

Aminocaproates↗
PubMed1989

Absorption kinetics of beta-alanine as model compound in rat small intestine.

Contradictory results have been reported on intestinal beta-alanine absorption, although a generalized view is that it could be a passive, nonmediated process. Since previous data from our laboratory suggested that some competition arises between intestinal absorption of the gamma-amino acidic drug baclofen and beta-alanine, a rat jejunum in situ study was undertaken in order to gain insight into the mechanism of beta-alanine absorption. Perfusion solutions with initial beta-alanine concentrations ranging from 0.3 to 56 mM were used. The beta-alanine absorption was clearly identified as a saturable process which obeys Michaelis-Menten equation kinetics, as assessed through two computer-assisted procedures based on differential and integrated forms of this equation. Parameter values found were: Vm = 3.88-4.72 mg.ml-1.h-1 (43.6-52.9 mM.h-1), and Km = 0.97-1.13 mg.ml-1 (10.9-12.7 mM). Statistical analysis does not account for the existence of significant parallel passive diffusion pathways (less than 0.2 h-1).

Alanine↗
PubMed1989

Non-linear intestinal absorption kinetics of cefadroxil in the rat.

Absorption of cefadroxil in a selective intestinal absorption area (the proximal third of the small intestine) of the anaesthetized rat, at seven initial perfusion concentrations, ranging from 0.01 to 10.0 mg mL-1, is shown to be a non-linear transport mechanism. With the aid of computer-fitting procedures based on differential and integrated forms of Michaelis-Menten equation, Vm and Km values of 36.7-37.3 mg h-1 and 12.0-13.0 mg, respectively, were found. The statistical parameters were better than those obtained both for first-order and for combined Michaelis-Menten and first-order kinetics. There is no evidence for substantial passive diffusion processes. The results reported here, together with allometric considerations and literature data analysis, may help to explain some particular non-linear features of plasma level curves associated with the administration of fairly high oral doses of cefadroxil to humans.

Animals↗
PubMed1987

Studies on the reliability of a bihyperbolic functional absorption model. II. Phenylalkylamines.

Evidence is given that demonstrates the reliability of the bihyperbolic equation, proposed by Plá-Delfina and Moreno, in fitting the correlation between absorption rate constants (ka) found in the small intestine and in the colon of the living anesthetized rat, and partition constants (1/RF-1), for a series of phenylalkylamines, a group of compounds which differ largely from others which have been tested. Emphasis is laid on the nonexistence of an optimum of lipophilicity for intestinal absorption/partition correlation: This feature makes inapplicable the probabilistic approaches to the reported data.

Aniline Compounds↗
PubMed1986

Studies on the reliability of a bihyperbolic functional absorption model. I. Ring-substituted anilines.

The present study reviews and checks the rearranged master lines of the functional bihyperbolic absorption model proposed by Plá-Delfina and Moreno, by examining the correlations between absorption rate constants experimentally found in the small intestine and in the colon of the rat, and two types of partition constants for a series of ring-substituted anilines, of low to medium molecular weight. Evidence is given which demonstrates the reliability of the bihyperbolic equation for the small intestine data, showing the importance of the type of substitution in the absorption rate of compounds; for the colonic data, the collapsed, monohyperbolic form of this equation (i.e., the Wagner-Sedman equilibrium model) applies, independent of the nature and position of the group substituents in the aniline molecule. This means that, as the bihyperbolic model equation predicts, aqueous pore diffusion is a crucial factor, as important as membrane permeation, in absorption in the small intestine, whereas in the colon only this latter route is operative. The perspectives opened by the application of the model to gastrointestinal absorption studies are also discussed.

Aniline Compounds↗
PubMed1986

Relationships between biophasic disposition and pharmacokinetic behavior in nonsteroid antiinflammatory drugs.

The time course of biophasic amounts of two nonsteroid antiinflammatory drugs (naproxen and oxyphenbutazone) after an intravenous dose of both drugs in rats (5 and 20 mg/kg, respectively) and their relationships with the drug amounts in central and peripheral compartments as defined through blood level data obtained after the same intravenous dose of the drug, are described. To assess the first point, the carrageenin-induced rat paw edema method is employed. Through previously established dose-response curves obtained after administration of different i.v. doses, the conversion of responses to biophasic amounts is achieved by means of the corresponding model equations. To calculate kinetic parameters through the fitting of the concentration-time data, a least-squares method based on the Marquardt algorithm is used on a computer. It can be concluded that the biophasic compartment cannot be identified as the "central" or the "peripheral" kinetic ones, being, however, the output biophasic rate constant not significantly different from the terminal disposition rate constant, beta or lambda 2.

Administration, Oral↗
PubMed1981

Intestinal absorption-partition relationships: a tentative functional nonlinear model.

Models and equations designed to elucidate passive intestinal absorption mechanisms by analysis of the relationship between the absorption rate constant (ka) and either the partition coefficients (P) or a related partition constant for homologous series of substances, are reviewed. Classical nonlinear physical models, such as those which assume the existence of a nonstirred layer or equilibrium extraction, predict sigmoidal or hyperbolic relationships between ka and P, whereas other models, which regard the membrane as a heterogeneous multicompartment system, predict parabolic or bilinear relationships between log ka and log P. In the present paper, an alternative model is proposed, which incorporates the Wagner-Sedman equilibrium extraction model together with the existence of pores, which play a fundamental role for compounds below 250 in molecular weight. Several apparently contradictory absorption-partition literature data are shown to be highly consistent with the tentative model proposed.

Diffusion↗