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Biomedical subjects

G L Amidon

Publications and source records attributed to G L Amidon.

At least 91 records · Page 5Linked to original sources
PubMed1995

Biology of membrane transport proteins.

Membrane transporter proteins are encoded by numerous genes that can be classified into several superfamilies, on the basis of sequence identity and biological function. Prominent examples include facilitative transporters, the secondary active symporters and antiporters driven by ion gradients, and active ABC (ATP binding cassette) transporters involved in multiple-drug resistance and targeting of antigenic peptides to MHC Class I molecules. Transported substrates range from nutrients and ions to a broad variety of drugs, peptides and proteins. Deleterious mutations of transporter genes may lead to genetic diseases or loss of cell viability. Transporter structure, function and regulation, genetic factors, and pharmaceutical implications are summarized in this review.

ATP-Binding Cassette Transporters↗
PubMed1995

A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability.

A biopharmaceutics drug classification scheme for correlating in vitro drug product dissolution and in vivo bioavailability is proposed based on recognizing that drug dissolution and gastrointestinal permeability are the fundamental parameters controlling rate and extent of drug absorption. This analysis uses a transport model and human permeability results for estimating in vivo drug absorption to illustrate the primary importance of solubility and permeability on drug absorption. The fundamental parameters which define oral drug absorption in humans resulting from this analysis are discussed and used as a basis for this classification scheme. These Biopharmaceutic Drug Classes are defined as: Case 1. High solubility-high permeability drugs, Case 2. Low solubility-high permeability drugs, Case 3. High solubility-low permeability drugs, and Case 4. Low solubility-low permeability drugs. Based on this classification scheme, suggestions are made for setting standards for in vitro drug dissolution testing methodology which will correlate with the in vivo process. This methodology must be based on the physiological and physical chemical properties controlling drug absorption. This analysis points out conditions under which no in vitro-in vivo correlation may be expected e.g. rapidly dissolving low permeability drugs. Furthermore, it is suggested for example that for very rapidly dissolving high solubility drugs, e.g. 85% dissolution in less than 15 minutes, a simple one point dissolution test, is all that may be needed to insure bioavailability. For slowly dissolving drugs a dissolution profile is required with multiple time points in systems which would include low pH, physiological pH, and surfactants and the in vitro conditions should mimic the in vivo processes.(ABSTRACT TRUNCATED AT 250 WORDS)

Biological Availability↗
PubMed1995

Gastric pH influences the appearance of double peaks in the plasma concentration-time profiles of cimetidine after oral administration in dogs.

The plasma concentration-time profiles of cimetidine often exhibit two peaks following oral administration of a single dose in the fasted state, while the concurrent administration of some antacids results in a lower extent as well as rate of absorption. In the present work, absorption of cimetidine after a single dose in the fasted state was studied as a function of gastric pH in male beagle dogs to determine whether gastric pH plays a role in the double peak phenomenon and/or can account for the decrease in bioavailability when antacids are coadministered. The extent of absorption of cimetidine was not influenced significantly by gastric pH, indicating that elevation of gastric pH is not the cause of decreases in the bioavailability of cimetidine when it is administered with antacids. Distinct double peaks or plateaux were noted in 8 of 10 plasma profiles when the gastric pH was 3 or below. Irregular absorption behavior was observed in 2 of 6 profiles in the pH range of 3 to 5, while single peaks were observed in all 10 profiles when the gastric pH was maintained at pH > or = 5. It was concluded that gastric pH is a major factor in the generation of cimetidine double peaks. Changes in gastric pH also resulted in changes in the apparent kinetics of absorption. Below pH 5, absorption mostly followed zero-order kinetics (9 of 16 profiles) or a more complex kinetic process involving at least two components to the absorption phase (5 of 16 profiles). At gastric pH > or = 5, however, absorption followed first order kinetics in 7 of 10 profiles. These differences in kinetics of absorption are postulated to arise from variations in gastric emptying as a function of pH and/or carryover effects of gastric pH into the upper intestine.

Absorption↗
PubMed1995

Gastrointestinal absorption of peptide drug: quantitative evaluation of the degradation and the permeation of metkephamid in rat small intestine.

The intestinal absorption of metkephamid (MKA), an analog of natural [Met]enkephalin, was investigated by means of vascular perfusion of the rat small intestine. Most of the MKA administered to the jejunal loop was degraded in the lumen by enzymatic hydrolysis, whereas only 0.3 to 1.2% of it was absorbed into the vascular flow. This means that enzymatic degradation is a major barrier against the intestinal absorption of MKA. The absorption of MKA was divided into two steps, degradation and permeation, and is expressed as clearance from the intestine. The degradation clearance (CLd) of MKA was 60- to 200-fold higher than the permeation clearance (CLp), indicating the rapid hydrolysis of MKA before absorption. The absorbed fraction of MKA increased with increasing luminal MKA concentration, mainly due to an increase in CLp rather than a decrease in CLd. MKA was degraded not only before absorption but also during permeation across the intestinal epithelium. Three kinds of enzyme inhibitors were co-administered with MKA into the intestinal loop. Puromycin, an aminopeptidase M inhibitor, markedly enhanced MKA absorption by both decreasing CLd and increasing CLp, indicating the predominant role of this enzyme in MKA degradation. Bestatin, another aminopeptidase M inhibitor, also effectively suppressed the degradation of MKA before absorption, whereas it only slightly increased CLp. It was further found that bestatin was less effective in inhibiting MKA hydrolysis during permeation. Thiorphan, an enkephalinase inhibitor, had no effect on MKA absorption.

Amino Acid Sequence↗
PubMed1994

Variable gastric emptying and discontinuities in drug absorption profiles: dependence of rates and extent of cimetidine absorption on motility phase and pH.

The influence of various fasting-state gastrointestinal parameters on variability in absorption of cimetidine was studied using simulation and cimetidine administration as a duodenal infusion and as an oral tablet in fistulated mongrel dogs. In the simulation studies, the frequency of double-peak occurrence in plasma profiles was estimated employing average gastric emptying rates as well as interdigestive-migrating-motor-complex (IMMC) phase lengths that were systematically altered. Emptying rates and phase lengths were modeled as periodic step functions. Simulations indicated that double peaks occur when gastric emptying of the drug begins in early phase I or late phase II/III, which represent the periods of very low, medium, and high gastrointestinal motility, respectively. The incidence is increased for longer phase-I duration and higher elimination rate constants. For a compound with a 2 h elimination or disposition half-life, two concentration maxima (double peaks) were found in 12% of the simulated concentration-time profiles. The double peak frequency in simulated curves was considerably higher for t1/2 < 30 min. When cimetidine was administered to dogs as a duodenal infusion in the active and quiescent motility phases, discontinuous profiles were observed, although the variability of the various parameters was reduced when compared. Pharmacokinetic models were set up that were characterized by multi-segmental input (one- to 3-lag-time models were used) for the profiles resulting from oral and duodenal administration. The lag time for the first process characterized the onset of absorption. A significant difference between phases was detected for infusions at pH 8, where the initial lag time was longer in the quiescent phase. The mean input time (MIT) was calculated as the integral input parameter. There was a tendency for the MIT to be higher for pH 6 infusions than for pH 4 and pH 8. Bioavailability analysis indicated that cimetidine was more rapidly and completely absorbed at pH 8 than at pH 6. Bioavailability was also slightly higher at pH 4 than at pH 6. We concluded that gastric emptying increased the variability of the cimetidine concentration-against-time profiles and that it plays a role with respect to double-peak occurrence, although it is only one of several causative factors.

Administration, Oral↗
PubMed1994

Viscoelastic properties of poly(ethylene oxide) solution.

The viscoelastic properties of poly(ethylene oxide) (PEO) solution were investigated using the dynamic oscillatory testing technique. With this technique, the effect of PEO molecular weight (MW), concentration, composition of mixed solvent systems consisting of propylene glycol, glycerol formal, and water, and the effect of NaCl salt on the viscoelastic properties of PEO solution were determined. Dynamic moduli (G1, G2), magnitude of complex viscosity (magnitude of eta*), and loss tangent (tan delta) were examined over a frequency range of 10(-3)-2.5 Hz at 30 degrees C. The results indicated that low MW PEOs show liquidlike behavior while high elasticity is exhibited by high MW PEOs due to entanglement formation. The complex viscosity, magnitude of eta*, exhibits shear thinning (power-law) characteristics under oscillatory measurements. The relationship between steady shear and complex viscosities follows the Cox-Merz rule over the shear rate and frequency region studied. Both the storage (G1) and loss (G2) modulus increase drastically as the proportion of water in the mixed solvent system increases. Similarly, both G1 and G2 are found to increase while the tan delta decreases with increasing concentration of PEOs. The addition of up to 2% w/w NaCl in an aqueous solution of 10% w/w 2 million MW PEO has no observed detrimental effect on the viscoelastic behavior.

Chemical Phenomena↗
PubMed1994

Modulated drug release using iontophoresis through heterogeneous cation-exchange membranes. 2. Influence of cation-exchanger content on membrane resistance and characteristic times.

An implantable drug delivery method using iontophoresis through cation-selective membranes was further developed. Heterogeneous cation-exchange membranes (HCMs) were prepared by mixing conductive sulfonated polystyrene beads into a nonconductive silicone rubber matrix. The membrane resistivity and lag time to steady-state transport of two salts, (+/-)-phenylpropanolamine hydrochloride (PPA) and NaCl, were evaluated during constant current iontophoresis at 37 degrees C as a function of the resin content in the HCMs. A continuous decline in membrane resistivity was observed as fractional resin content (l) was increased over the entire usable region (l = 0.29-0.52), a characteristic that could be described by a percolation scaling law (for an infinite lattice, 3-D geometry). Morphological analysis of the membranes before and after swelling strongly suggested that the conducting clusters of resin beads form during the swelling period prior to use. The response time to steady-state transport of PPA into NaCl during a 40 microA constant current (0.27 cm2) was found to increase with increasing l, but not without decreasing the permselectivity of the HCMs for the drug cation. The lag time effect could be explained in terms of an increasing number of fixed charge groups in the membrane available for transport (mfcA), which was derived from a macroscopic mass balance model. The values of mfcA were also found to be related to the characteristic time of diffusion in a homogeneous transport projection of the HCM (or an effective medium), an essential parameter for future non-steady-state simulations. The characteristic time of diffusion was found to be invariant with changing resin content, suggesting that the membranes are fairly nontortuous (ca. seven beads thick). By assuming that the thickness of the HCM approaches the thickness of its homogeneous projection, an expression was derived to predict lag time to steady-state PPA transport requiring resistance measurements only (provided that the resin capacity is known). There was excellent agreement between the theoretical and experimental lag time to steady-state transport of PPA (r = 0.96, p < 0.001), further implicating the role of membrane resistance in the bi-ionic system. These modeling approaches have already found utility in iontophoretic implant design for prevention of cardiac arrhythmias and may be valuable in future non-steady-state analysis to further develop on-line detection-implant response technology.

Cations↗
PubMed1994

The role of rheological properties in mucociliary transport by frog palate ciliated model.

The effect of viscoelastic properties on mucociliary transport rate was investigated using the frog palate ciliated model. Mucociliary transportability of several hydrophilic polymeric gels with widely different viscoelastic characteristics were tested on the frog palate mucociliary model. An apparent negative relationship is observed between the relative transport rate (TR) and storage (G1) or loss (G2) modulus. However, a minimum in relative transport rate is observed at an apparent loss tangent (tan delta) value of between 0.7 and 0.9. A theoretical model for mucociliary transport is presented. The model predicted a minimum in transport rate at tan delta equal to 1.74 after adjustment for primary variation due to storage modulus (G1), which is in agreement with the observed frog palate transport rate. The model isolates the loss tangent (tan delta) and the magnitude of the complex modulus (magnitude of G*) as the important viscoelastic parameters for mucociliary transport. Optimum rheological characteristics with respect to slow transport rate can be achieved by using hydrophilic polymer gels with a large complex modulus and simultaneously with a loss tangent equal to 1.74.

Animals↗
PubMed1994

Oral absorption of peptides: the effect of absorption site and enzyme inhibition on the systemic availability of metkephamid.

In this study the intestinal degradation and absorption of a synthetic pentapeptide, metkephamid, were investigated in the rat by determination of its wall permeabilities in the small and large intestine and the extent and mechanism of its intestinal degradation. The peptide was metabolized in the gut wall through contact with membrane-bound enzymes in the brush border membrane. The extent of metabolic inactivation depended on the intestinal segment investigated and decreased in the axial direction. No metabolism was found in the colon. The dimensionless wall permeabilities (Pw*), determined by single-pass perfusion, were also site dependent. Pw* was highest in the ileum [1.91 +/- 0.24, (SE); n = 4], followed by the jejunum (1.64 +/- 0.34; n = 4) and the colon (0.67 +/- 0.38; n = 4). Based on the permeability data alone and under the assumption of no presystemic metabolism, complete bioavailability would be predicted for metkephamid. However, following oral administration, the mean absolute bioavailability was only 0.22 +/- 0.065% (n = 3), indicating the overall dominance of degradation in the absorption process. Thus future strategies in oral peptide delivery should focus on increasing the stability of the peptide in the intestine by modifying the peptide structure and/or delivering the compound to an intestinal segment showing little or no enzymatic degradation.

Amino Acid Sequence↗
PubMed1994

Noncompetitive inhibition of cephradine uptake by enalapril in rabbit intestinal brush-border membrane vesicles: an enalapril specific inhibitory binding site on the peptide carrier.

ACE inhibitors, as well as aminocephalosporins with peptide-like structures, are transported by the intestinal peptide carrier. We investigated the transport mechanism using intestinal brush-border membrane vesicles from rabbits and observed that enalapril, an angiotensin converting enzyme inhibitor and substrate of the peptide carrier, noncompetitively inhibited the uptake of cephradine, an aminocephalosporin and substrate of the peptide carrier, with an inhibition constant (Ki) of 2.6 mM when it was present on the cis side (outside) of the vesicles. By contrast, enalaprilat, cefadroxil and GlyPro competitively inhibited cephradine transport with Ki values of 5.4, 3.8 and 5.1, respectively. These results suggest the presence of an enalapril-specific inhibitory binding site on the peptide carrier. In addition, enalapril on the trans side (inside) of the vesicles inhibited the uptake of cephradine, suggesting an apparent reduction of carrier availability by a trapping mechanism. On the other hand, cefadroxil stimulated the uptake of cephradine in the trans experiment, consistent with the concept of countertransport. These findings reveal the uniqueness of enalapril regarding its mode of interaction with the peptide carrier(s) which has been of increasing interest regarding its role in the intestinal absorption of peptide-type drugs.

Animals↗
PubMed1993

Description and simulation of a multiple mixing tank model to predict the effect of bile sequestrants on bile salt excretion.

A nonlinear, multicompartment mixing tank model based on human physiologic parameters from the literature and in vitro bile salt sequestrant binding parameters was integrated numerically to simulate bile salt excretion. The model focuses on the transit of bile salts and resin, bile salt binding, and bile salt reabsorption as a means of gaining insight into the functioning of bile sequestrants in the gastrointestinal tract and the effect of reabsorption of bile salts on the sequestering process. The series of compartments through the ileal region were tested over a range of parameter values, and the results were compared with bile salt output from ileostomy patient data to validate the model without resin. In simulations incorporating resin with a reversible binding scheme, fecal bile salt output was 2.37 (+/- 0.6) x 10(-3) mol/day compared with 2.64 (+/- 1.1) x 10(-3) mol/day for human data. Assuming irreversible bile salt binding resulted in predictions of fecal bile salt excretion greater than three times physiologic values. The results of these simulations support the hypothesis that the lack of efficacy of bile sequestrants is due to the displacement of bound bile salts from the sequestrant as a consequence of anion competition and bile salt reabsorption. Gastric emptying effects and the timing of resin doses have also been investigated with the model.

Bile↗
PubMed1993

Characterization of the oral absorption of some beta-lactams: effect of the alpha-amino side chain group.

The intestinal absorption mechanisms of cefixime, 7-aminocephalosporanic acid (7-ACA) and 6-aminopenicillanic acid (6-APA) were determined from the results of single-pass perfusion experiments in rats by modified boundary layer analysis. The estimated absorption parameters (SEM) were as follows: for cefixime, J*max = 0.016 (0.008) mM, Km = 0.031 (0.015) mM, P*m = 0.184 (0.037), P*c = 0.523 (0.051); for 7-ACA, J*max = 6.39 (1.57) mM, Km = 19.33 (5.64) mM, P*c = 0.33 (0.03) mM; and for 6-APA, P*m = 0.41 (0.11), where J*max is the maximal flux of peptide transport system, Km is the intrinsic Michaelis constant, P*m is the dimensionless membrane permeability, and P*c is the dimensionless carrier permeability. Cefixime was absorbed by a carrier-mediated mechanism because its wall permeability (P*w) was concentration dependent and significantly inhibited by cephradine. A concentration-dependent permeability of 7-ACA was observed, but an inhibition study failed to show significant inhibition by cephradine. The absorptions of 6-APA and penicillin V were not inhibited by cephradine or cefixime. The fractions of dose absorbed of several beta-lactam antibiotics correlated well with their absorption numbers obtained from P*w values in rats. These results further demonstrate that an alpha-amino group is not necessary for transport by the intestinal peptide transporter.

Administration, Oral↗
PubMed1993

Peptide carrier-mediated transport in intestinal brush border membrane vesicles of rats and rabbits: cephradine uptake and inhibition.

The uptake kinetics of cephradine, an amino-beta-lactam antibiotic, were studied in rat and rabbit intestinal brush border membrane vesicles preparations using both the Ca2+ and the Mg2+ methods of preparation, in the presence of an inward proton gradient. The Ca2+ method demonstrated greater uptake of cephradine in intestinal brush border vesicles prepared from both rat and rabbit and was used for these studies. The transport was observed to be of Michaelis-Menten carrier-mediated type with a passive transport component. The kinetic parameters obtained were as follows: for rat and rabbit, respectively, Km, 1.6 and 1.9 mM; Jmax', 1.7 and 20.7 nmol/mg/min; Pc' (= Jmax'/Km), 1.1 and 10.9 microL/mg/min; and Pm', 0.4 and 0.8 microL/mg/min. The kinetic parameters for the rat vesicles are consistent with those from our previous perfusion study using a conversion factor of 0.71 cm2/mg protein. The rabbit vesicles exhibited a similar Michaelis constant and a 10-fold larger maximal transport velocity, suggesting a quantitative advantage for the study of carrier-mediated transport in the rabbit compared to rat vesicles from the intestine. Cephradine uptake was inhibited by phenylpropionylproline, a proline derivative, and enalapril, an ACE inhibitor, which do not have an alpha-amino group, as well as dipeptides, tripeptides, and amino-beta-lactam antibiotics in both rat and rabbit vesicles. These results support the suggestion that they share the same peptide carrier pathway for oral absorption and that the vesicles may be a useful tool in developing orally effective peptide-type drugs.

Alkaline Phosphatase↗
PubMed1993

Viscoelasticity of anionic polymers and their mucociliary transport on the frog palate.

The influence of formulation variables on the rheology of polyanionic formulations and the relationships between viscoelastic properties and mucociliary transport rate were investigated. Polymeric samples were oscillated from 0.001 to 5 Hz using either a "cone and plate" or a "coaxial cylinder" measuring system. The mucociliary transport rates of polymeric samples were determined and compared movement of charcoal powder on the frog palate. For the linear polymeric solutions, sodium carboxymethylcellulose and sodium alginate, the elastic modulus (G') increased with increasing amplitudes during frequency scan. However, the G' or viscous modulus (G'') of partially cross-linked polyacrylic acid (cPAA) samples did not change significantly under oscillation. Both G' and G'' of cPAA samples were significantly influenced by the amount of salt present in the formulation. The rheology of 2% (w/w) cPAA in 90:10 (w/w) propylene glycol:alcohol changed from a viscous fluid to a coarse suspension after neutralization. The pH increased gradually when the nonaqueous formulation reacted with water and the maximum dynamic moduli were obtained after incorporating 20% (w/w) water in the formulation. A negative correlation was found between the G' of linear polyanionic samples and the relative transport rate. However, the lowest mucociliary transport rate was observed when the loss tangent (G''/G') was around 0.4-0.5.

Acrylic Resins↗