0000000000276490
AUTHOR
J.m. Plá-delfina
Non-linear Intestinal Absorption Kinetics of Cefadroxil in the Rat
Abstract 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 h…
Kinetic Characterization of Secretory Transport of a New Ciprofloxacin Derivative (CNV97100) across Caco-2 Cell Monolayers**This work has been submitted for the partial fulfillment of the requirement for a Ph.D. Degree in Pharmaceutics at the University of Valencia, Valencia, Spain
The kinetics of transport of a new fluoroquinolone antibiotic (CNV97100) and its analogs were characterized using the Caco-2 cell culture model. Unidirectional permeabilities of these analogs were greater (p < 0.05) than that of ciprofloxacin. The absorptive permeabilities (P(AB)) of 4'-N-substituted analogs (CNV97101-104) were 400-600% greater, whereas the secretory permeability (P(BA)) was 25-80% greater than unsubstituted analogs because CNV97101-104 were poor substrates for efflux transporters (efflux ratio approximately 1). The transport of compounds without 4'-N-substitution (i.e., ciprofloxacin and CNV97100) favored secretion (efflux ratio approximately 4). Further characterization o…
Activity–Bioavailability balance in Oral Drug Development for a Selected Group of 6‐Fluoroquinolones
Abstract 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 concentrati…
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 a…
Compared effects of synthetic and natural bile acid surfactants on xenobiotic absorption I. Studies with polysorbate and taurocholate in rat colon
Some expected differences between synthetic and natural bile acid surfactants relative to their influences on xenobiotic absorption are briefly outlined on the basis of literature data. Then, experimental work is presented which shows that these differences exist and that they can be even more relevant than suspected. Absorption tests were developed in rat colon in situ with polysorbate (synthetic) and sodium taurocholate (natural) surfactants, using a homologous series of phenylalkylcarboxylic acids as test compounds. At the critical micelle concentration (CMC), the two previously reported actions of synthetic surfactants on xenobiotic absorption (i.e. the increase in absorbing membrane po…
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 a…
A novel approach to determining physicochemical and absorption properties of 6-fluoroquinolone derivatives: experimental assessment
The ToSS MoDe approach is used to estimate the n-octanol/buffer partition coefficient, the apparent intestinal absorption rate constant and intestinal permeability from a 6-fluoroquinolone data set. Improved in silico methods for predicting a drug's ability to be transported across biological membranes and other biopharmaceutical properties is highly desirable to optimize new drug development. The physicochemical property (Log P) of 26 6-fluoroquinolone derivatives and the absorption properties (Log K(a) and Log P(eff)) of 21 derivatives were well described by the present approach. The models obtained confirm the important role of lipophilicity in the absorption process and its relation wit…
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 = 2.4…
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 s…
Pharmacokinetics and bioavailability of diclofenac in the rat.
Diclofenac sodium is a widely used drug with interesting absorption and disposition features when administered to laboratory animals. The present study was undertaken to assess the pharmacokinetics of the drug after iv and gastrointestinal dosing to rats. Renal excretion of unchanged drug was negligible, but biliary excretion of the drug (unchanged and conjugated) was detected in bile duct-cannulated rats; it accounted for 27.2 and 31.2% of the total dose following iv and intraduodenal administration, respectively. Most of the drug excreted in the bile was conjugated diclofenac; unchanged drug accounted for only 4.7 and 5.4% of total diclofenac excreted in the bile after iv and intraduodena…
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 Pla-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/R.F−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.
Evidence of a specialized transport mechanism for the intestinal absorption of baclofen
Absorption of the spasmolytic drug baclofen in three selected intestinal segments of living anaesthetized rats in situ, is shown to be a specialized transport mechanism obeying Michaelis-Menten kinetics. Equation parameters were calculated through different procedures, whose features are discussed. A computer method based on the integrated form of Michaelis-Menten equation which reproduces the entire time course of drug absorption from the data found in three intestinal perfusion series at different initial concentrations, yielded Vm and Km values of 12.0 mg h-1 and 8.0 mg, respectively, in the mean segment of the small intestine, a rather selective absorption site for baclofen. Lesser but …
Kinetics of the intestinal uptake of zinc acexamate in normal and zinc-depleted rats.
Abstract 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 smal…
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 w…
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…
Compared effects of synthetic and natural bile acid surfactant on xenobiotic absorption. II. Studies with sodium glycocholate to confirm a hypothesis
Abstract The effects of sodium glycocholate (SGC) on the intestinal absorption of drug-related xeriobiotics are investigated, on the basis of previously established absorption/partition relationships. Six phenylalkylcarboxylic acids, closely related to nonsteroid anti-inflammatory drugs in structure and constituting a true homologous series, were used as test compounds through an in situ rat gut technique, using the whole colon as nonspecialized absorption membrane model. Whereas the synthetic surfactants (i.e., polysorbates and laurylsulphates) at the critical micelle concentration have been shown to disrupt the aqueous boundary layer adjacent to the membrane, SGC does not; in contrast, it…
Consistency of Carbopol 971-P NF gels and influence of soluble and cross-linked PVP.
A study is made of the polymerization process of polyacrylic acid, commercially known as Carbopol® 971 NF, assessing its consistency as a function of the degree of neutralization at pH values from 3 to 12, approximately. Percentage concentrations ranging from 0.1 to 1.4% (w/w) were studied. The gels obtained were non-Newtonian, and pseudoplastic. As concentration and pH rise, the consistency of the gels increase to a maximum, which appears between pH 6 and 8, allowing their use as vehicles in bioadhesive formulations for mucosal application. Over the increasing viscosity interval, functions were obtained to indicate the consistency of the gel as a function of pH and concentration. Since the…
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 intrave…