0000000000174359
AUTHOR
A. Martín-villodre
Partition Behavior of Anilines in Bulk‐Phase and High‐Performance Liquid Chromatographic Systems: Influence on Correlation with Biological Constants
Abstract The partition behavior of a mixed series of ring‐substituted anilines in reversed‐phase high‐performance liquid chromatographic systems is substantially different from that observed in a classical bulk‐phase partition system with n ‐heptane as the aprotic reference solvent. On the basis of the equivalence of each ring substituent in the p ‐straight‐chain methylene groups (ν value) as a function of the fraction of organic solvent (acetonitrile or methanol) in the mobile phase, the biased partition behavior for imperfect homologues and heterologues is verified relative to that of perfect homologues. This behavior was tentatively attributed, mainly, to differences in the hydrogen bond…
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…
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…
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…
Labetalol absorption kinetics: Rat small intestine and colon studies
Labetalol is a widely used drug for the management of hypertension, which is preferably administered by the oral route despite its low bioavailability. The objective of this study is to ascertain the mechanisms underlying its absorption as an approach to help in predicting the influence of dosage changes, possible drug-drug and drug-fruit juice interactions. Perfusion experiments have been performed in rats in two sites of absorption: the intestine and the colon. The nonlinearity of the process has been established by means of the assay of a wide range of concentrations (2-2000 microM). Fitting of the concentration versus time data allows the estimation of passive diffusion constant in the …
In Vitro Percutaneous Penetration of Acyclovir from Solvent Systems and Carbopol 971-P Hydrogels: Influence of Propylene Glycol
The mechanism underlying propylene glycol (PG) effects on acyclovir (ACV) penetration through human epidermis were studied. Solvent systems and Carbopol gels containing increasing percentage of PG (from 0% to 70%, w/w) were used. Viscosity studies of both vehicles were carried out to characterise the influence of rheological behaviour. In solvent systems skin permeation values of ACV increase as the concentration of PG increase yielding a maximum enhancement ratio (ER = 10) for 70% PG. The release rate of ACV from gels was determined. Higuchi's model was used to estimate the apparent diffusion coefficient of the drug. These values show a decrease as the content of PG in the vehicle increase…
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 …
Profile of P-glycoprotein distribution in the rat and its possible influence on the salbutamol intestinal absorption process.
8 pages, 2 figures, 2 tables.--PMID: 15124220 [PubMed]
The influence of active secretion processes on intestinal absorption of salbutamol in the rat.
Abstract Salbutamol was perfused in the small intestine of rat using a standard rat gut ‘in situ’ preparation: (1) in inhibitor-free solution at seven different concentrations (0.15, 0.29, 1.20, 5.0, 9.0, 13.0 and 18.0 mM); (2) at a 0.29 mM concentration – thought to be close to the allometric dose in man – in the presence of a non-specific enzyme inhibitor, sodium azide (0.3, 3.0 and 6.0 mM); and (3) at 0.29 mM in the presence of a selective secretion inhibitor, verapamil (10.0 and 20.0 mM). In free solution, the mixed-order rate constants, k ′ a , of salbutamol increase as the solute concentration increases until an apparent asymptotic value is reached. This could be due to the saturation…
Modelling intestinal absorption of salbutamol sulphate in rats
The objective was to develop a semiphysiological population pharmacokinetic model that describes the complex salbutamol sulphate absorption in rat small intestine. In situ techniques were used to characterize the salbutamol sulphate absorption at different concentrations (range: 0.15-18 mM). Salbutamol sulphate at concentration of 0.29 mM was administered in presence of verapamil (10 and 20 mM), grapefruit juice and sodium azide (NaN3) (0.3, 3 and 6 mM). Different pharmacokinetic models were fitted to the dataset using NONMEM. Parametric and non-parametric bootstrap analyses were employed as internal model evaluation techniques. The validated model suggested instantaneous equilibrium betwee…
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…
Absorption-partition relationships for true homologous series of xenobiotics as a possible approach to study mechanisms of surfactants in absorption. IV. Phenylacetic acid derivatives and anionic surfactants
Abstract This paper — the latest in this series of reports — deals with the effects of the anionic surfactant sodium lauryl sulfate on the colonic absorption of acidic xenobiotics (phenylalkylcarboxylic acids), as compared with those exerted by the nonionic polysorbate 80. The effects of these surfactants are qualitatively identical but quantitatively different. Thus, the increase in polarity of the colonic absorbant membrane is greater with lauryl sulfate, whereas micellar solubilization is much higher with polysorbate. As for the rest (i.e. the elimination of the stagnant aqueous diffusion layer as a limiting step for absorption), the two surfactants behave in a similar way. The biopharma…