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  • 1
    Electronic Resource
    Electronic Resource
    Impact of Regional Intestinal pH Modulation on Absorption of Peptide Drugs: Oral Absorption Studies of Salmon Calcitonin in Beagle Dogs (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1233-1239 
    Details
    ISSN: 1573-904X
    Keywords: intestinal pH recovery ; oral absorption ; peptide drugs ; salmon calcitonin ; dogs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To investigate the relationship between the modulation of intestinal pH and the oral absorption properties of a model peptide drug, salmon calcitonin (sCT), in conscious beagle dogs. Methods. Studies were performed to characterize the disintegration of the formulation, intestinal pH changes, and the appearance of the peptide in the blood. Enteric-coated formulations containing sCT and various amounts of citric acid (CA) were tethered to a Heidelberg capsule (HC) and given orally to normal beagle dogs. Blood samples were collected and analyzed by radioimmunoassay (RIA). Intestinal pH was continuously monitored using the Heidelberg pH capsule (HC) system. The integrity of the HC-delivery system tether was verified by fluoroscopy. Results. The intra-individual variation in gastric emptying (GE) of the delivery system was large. There were also large inter-individual differences in the disintegration and absorption properties of the various formulations. However, the peak plasma concentrations of sCT were always observed when the intestinal pH declined. The average baseline intestinal pH was 6.1 ± 0.2 (mean ± SEM, n = 12). The intestinal pH reduction was 2.6 ± 0.4 (mean ± SEM, n = 12, ranged from 0.5 to 4.0 units from baseline). There was a good correlation between the time to reach the trough intestinal pH (tpH,min) and time to reach the peak plasma concentration (tconc,max) of sCT (tconc,max = 0.95 × tpH,min + 14.1, n = 11, r2 = 0.91). Plasma Cmax and area under the curve (AUC) increased with increasing amounts of CA in the formulations. Conclusions. The results of these studies demonstrate that the oral absorption properties of a model peptide drug, sCT, can be modulated by changing intestinal pH. sCT is a substrate for the pancreatic serine protease trypsin which has maximal activity at pH 5 to 6. Reducing intestinal pH presumably stabilizes sCT in the GI tract enabling greater absorption of the intact peptide.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1014849630520
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  • 2
    Electronic Resource
    Electronic Resource
    Determining Intestinal Metabolism and Permeability for Several Compounds in Rats. Implications on Regional Bioavailability in Humans (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 108-113 
    Details
    ISSN: 1573-904X
    Keywords: Bioavailability ; captopril ; didanosine ; intestinal permeability ; mannitol ; metabolism ; ofloxacin ; regional oral absorption ; site-specific ; zidovudine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To investigate the regional differences in small intestinal (SI) metabolism and permeability for several compounds and to ascertain the potential significance of these differences on the reported reductions in regional bioavailability in humans. Methods. The regional SI metabolism and permeability of captopril, didanosine (ddl), mannitol, ofloxacin and zidovudine (ZDV) were investigated in rats using a Single Pass Intestinal Perfusion (SPIP) procedure or intestinal homogenates. Results. ddI was metabolized to a greater extent in the upper SI whereas captopril was metabolized to a greater extent in the lower SI. Relatively low homogenate concentrations resulted in significant degradation of captopril in the upper and lower SI. All other compounds were stable and changes in the buffer system or the initial concentration did not affect the results. The SI permeabilities of all compounds, with the exception of mannitol, decreased linearly with respect to SI location and the slopes of the corresponding normalized regression lines were not significantly different. Conclusions. It has been reported that captopril and ddl demonstrate regional intestinal bioavailability in several species including humans. The current results suggest that the reported reduction in the lower SI bioavailability of captopril may be a result of a reduction in permeability and an increase in intestinal metabolism whereas for ddl, the reduction in the lower SI bioavailability appears to be attributable to a reduction in intestinal permeability. Other factors such as luminal metabolism may also significantly effect regional differences in the intestinal bioavailability of ddl or captopril. Based on these results, a strong possibility exists that ofloxacin and ZDV may also demonstrate regional differences in intestinal bioavailability.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016041620024
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  • 3
    Electronic Resource
    Electronic Resource
    Evidence for Diminished Functional Expression of Intestinal Transporters in Caco-2 Cell Monolayers at High Passages (1997)
    Springer
    Pharmaceutical research 14 (1997), S. 757-762 
    Details
    ISSN: 1573-904X
    Keywords: aqueous boundary layer ; brush border enzymes ; carrier-mediated transport ; diffusion chamber ; heterogeneity ; permeability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To investigate the effects of passaging on the intrinsic membrane transport parameters of compounds absorbed by means of passive and carrier-mediated processes in the Caco-2 cell line. Methods. Caco-2 cells at low (28−36) and high (93−108) passage numbers were used to evaluate the transport characteristics of model compounds for paracellular diffusion (mannitol), transcellular diffusion (progesterone) and carrier-mediated transport (cephalexin, cephradine, phenylalanine, proline, and taurocholic acid) using side-by-side diffusion chambers. Intrinsic intestinal transport parameters were determined by correcting the effective permeability for potential biases introduced by the microporous filter and aqueous boundary layer. Intrinsic maximal flux (J max, Michaelis constant (K m) and carrier permeability (P c) were determined as a function of passage number. Results. Compared to the low passaged cells, the high passaged Caco-2 cells were characterized by less morphological heterogeneity, higher transepithelial electrical resistance, higher transcellular diffusion, lower paracellular diffusion, lower carrier-mediated transport and lower alkaline phosphatase activity. The use of effective transport parameters overestimated the K m and underestimated P c but had no effect on J max. Conclusions. The current results provide experimental evidence that the passaging process significantly affects the biological characteristics and transport properties of Caco-2 cell monolayers. The effects are consistent with a reduction in the functional expression of a brush border enzyme and several transport proteins as passage number is increased. The underlying basis for this appears to be a selection of fast-growing subpopulations from the original heterogeneous Caco-2 cell line during passaging.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1012150405949
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  • 4
    Electronic Resource
    Electronic Resource
    Characterization of the Regional Intestinal Kinetics of Drug Efflux in Rat and Human Intestine and in Caco-2 Cells (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1160-1167 
    Details
    ISSN: 1573-904X
    Keywords: intestinal transport kinetics ; drug efflux ; jejunum ; ileum ; colon ; Caco-2 cells ; vinblastine sulphate ; verapamil hydrochloride ; etoposide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The aim of the present study was to investigate the transport kinetics of intestinal secretory processes in the jejunum, ileum and colon of rats and humans and in Caco-2 cells, in vitro. Methods. Etoposide, vinblastine sulphate and verapamil hydrochloride were chosen as model substrates since they have been reported to undergo efflux in various other tissues. The concentration dependence, inhibition, directionality, temperature dependence, proton/sodium dependence, and ATP dependence of efflux were studied using side-by-side diffusion chambers and brush border membrane vesicles (BBMVs). Intestinal tissue from rats and humans and Caco-2 cells (passage no. 26) were used. Directional steady state effective permeabilities were calculated from drug appearance in the apical (AP) or basolateral (BL) chambers. Kinetic studies were carried out by investigating substrate efflux at concentrations ranging from 0.2 μM to 1000 μM. Since substrate efflux may be a result of more than one transporter, the hybrid efflux Km (Michaelis-constant), Pc (carrier-mediated permeability), and Pm (passive permeability) were determined as a function of intestinal region. Inhibitor studies were performed using quinidine (0.2 mM), a mixed inhibitor of P-glycoprotein (Pgp) and Multidrug Resistance-Associated Protein (MRP), and Leukotriene C4(100 nM), an inhibitor of MRP and the canalicular multispecific organic anion transporter (cMOAT). Temperature dependent efflux was determined by investigating the BL to AP transport at temperatures ranging from 3°C to 37°C. Energies of activation (Ea) were determined from an Arrhenius analysis. Sodium, proton, and ATP dependence were determined using BBMVs. Immunoquantitation of Pgp, MRP and Lung Resistance Protein (LRP) in Caco-2 cells were carried out using Western blot analysis. Results. Active efflux of all substrates was observed in all regions of rat and human intestine and in Caco-2 cells. Directionality was observed with BL to AP transport exceeding AP to BL transport. The BL to AP/AP to BL permeability ratio, the efflux ratio, ranged from 1.4 to 19.8. Heal efflux was significantly higher (p 〈 0.001) than in other regions. Kinetic studies revealed that hybrid efflux Km values ranged from 4 to 350 μM. In some cases, efflux was not saturable due to the solubility limits of the compounds utilized in this study. In presence of inhibitors, efflux ratios approached 1. BL to AP transport was temperature dependent in rat ileum for all substrates. Ea of intestinal efflux was found to be 11.6, 8.3, and 15.8 kcal/mole for etoposide, vinblastine and verapamil, respectively, suggesting an active, energy-dependent efflux mechanism. Substrate efflux was not sodium or proton dependent but was dependent on ATP. Using Western blot analysis the presence of Pgp, MRP, and LRP was demonstrated in Caco-2 cells and the amount of each transport protein varied as a function of passage number. Conclusions. Using multiple putative efflux substrates, the current results demonstrate that intestinal efflux was regionally dependent, mediated by multiple efflux transporters, the Km’s were in the micro-molar range, and involved an energy dependent mechanism(s).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011971303880
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  • 5
    Electronic Resource
    Electronic Resource
    Biopharmaceutical Approaches for Developing and Assessing Oral Peptide Delivery Strategies and Systems: In Vitro Permeability and In Vivo Oral Absorption of Salmon Calcitonin (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 527-533 
    Details
    ISSN: 1573-904X
    Keywords: permeability ; bioavailability ; rats ; dogs ; humans ; oral delivery ; peptides ; and salmon calcitonin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To evaluate a biopharmaceutical approach for selecting formulation additives and establishing the performance specifications of an oral peptide delivery system using sCT as a model peptide. Methods. The effect of formulation additives on sCT effective permeability and transepithelial electrical resistance (TEER) was evaluated in side-by-side diffusion chambers using rat intestinal segments. Baseline regional oral absorption of sCT was evaluated in an Intestinal and Vascular Access Port (IVAP) dog model by administration directly into the duodenum, ileum, and colon by means of surgically implanted, chronic catheters. The effect of varying the input rate and volume of the administered solution on the extent of sCT absorption was also evaluated. Citric acid (CA) was utilized in all studies to cause a transient reduction in local pH. In vitro samples and plasma samples were analyzed by radioimmunoassay (RIA). Two oral delivery systems were prepared based on the results of the in vitro and IVAP studies, and evaluated in normal dogs. Results. Maximal permeability enhancement of sCT was observed using taurodeoxycholate (TDC) or lauroyl carnitine (LC) in vitro. Ileal absorption of sCT was higher than in other regions of the intestine. Low volume and bolus input of solution formulations was selected as the optimal condition for the IVAP studies since larger volumes or slower input rates resulted in significantly lower sCT bioavailability (BA). Much lower BA of sCT was observed when CA was not used in the formulation. The absolute oral bioavailability (mean ± SD) in dogs for the control (sCT + CA) and two proprietary sCT delivery systems was 0.30% ± 0.05%, 1.10 ± 0.18%, and 1.31 ± 0.56%, respectively. Conclusions. These studies demonstrate the utility of in vitro evaluation and controlled in vivo studies for developing oral peptide delivery strategies. Formulation additives were selected, the optimal intestinal region for delivery identified, and the optimal release kinetics of additives and actives from the delivery system were characterized. These methods were successfully used for devising delivery strategies and fabricating and evaluating oral sCT delivery systems in animals. Based on these studies, sCT delivery systems have been fabricated and tested in humans with favorable results.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018819012405
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  • 6
    Electronic Resource
    Electronic Resource
    Mass Balance Approaches for Estimating the Intestinal Absorption and Metabolism of Peptides and Analogues: Theoretical Development and Applications (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 271-275 
    Details
    ISSN: 1573-904X
    Keywords: extent of absorption ; mass balance ; intestinal metabolism ; cefaclor ; cefatrizine ; chymotrypsin ; insulin ; peptides
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A theoretical analysis for estimating the extent of intestinal peptide and peptide analogue absorption was developed on the basis of a mass balance approach that incorporates convection, permeability, and reaction. The macroscopic mass balance analysis (MMBA) was extended to include chemical and enzymatic degradation. A microscopic mass balance analysis, a numerical approach, was also developed and the results compared to the MMBA. The mass balance equations for the fraction of a drug absorbed and reacted in the tube were derived from the general steady state mass balance in a tube: dM/dZ = {[(2/R)(P w + k r)]CV L}/v z, where M is mass, z is the length of the tube, R is the tube radius, P w is the intestinal wall permeability, k r is the reaction rate constant, C is the concentration of drug in the volume element over which the mass balance is taken, V L is the volume of the tube, and v z is the axial velocity of drug. The theory was first applied to the oral absorption of two tripeptide analogues, cefaclor (CCL) and cefatrizine (CZN), which degrade and dimerize in the intestine. Simulations using the mass balance equations, the experimental absorption parameters, and the literature stability rate constants yielded a mean estimated extent of CCL (250-mg dose) and CZN (1000-mg dose) absorption of 89 and 51%, respectively, which was similar to the mean extent of absorption reported in humans (90 and 50%). It was proposed previously that 15% of the CCL dose spontaneously degraded systemically; however, our simulations suggest that significant CCL degradation occurs (8 to 17%) presystemically in the intestinal lumen. Insulin (M r = 5700), which is metabolized in the intestine primarily by α-chymotrypsin, was chosen for the second application of theory. The simulations show that the intestinal absorption of insulin is approximately 1% of the administered dose. Further, the extent of insulin oral absorption may not exceed 2% even if effective enzyme inhibitors are dosed concurrently since simulations show that insulin absorption is permeability limited. The steady-state macroscopic and microscopic simulation results were comparable and, for the antibiotics, were similar to published clinical results. Therefore, both approaches are useful for estimating the extent of oral peptide absorption and intestinal reaction from in vitro and in situ results.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018999130076
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  • 7
    Electronic Resource
    Electronic Resource
    Characterization of the Oral Absorption of β-Lactam Antibiotics. I. Cephalosporins: Determination of Intrinsic Membrane Absorption Parameters in the Rat Intestine In Situ (1988)
    Springer
    Pharmaceutical research 5 (1988), S. 645-650 
    Details
    ISSN: 1573-904X
    Keywords: colon ; concentration dependent absorption ; intrinsic permeability ; jejunum ; nonpassive absorption ; unstirred layer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The oral absorption of five cephalosporin antibiotics, cefaclor, cefadroxil, cefatrizine, cephalexin, and cephradine, has been studied using a single-pass intestinal perfusion technique in rats. Intrinsic membrane absorption parameters, “unbiased” by the presence of an aqueous permeability (diffusion or stagnant layer), have been calculated utilizing a boundary layer mathematical model. The resultant intrinsic membrane absorption parameters are consistent with a significant carrier-mediated, Michaelis-Menten-type kinetic mechanism and a small passive component in the jejunum. Cefaclor colon permeability is low and does not exhibit concentration dependent behavior. The measured carrier parameters (±SD) for the jejunal perfusions are as follows: cefaclor, J max * = 21.3 (±4.0), K m = 16.1 (±3.6), P m * = 0, and P c *= 1.32 (±0.07); cefadroxil, J max * = 8.4 (±0.8), K m = 5.9 (±0.8), P m * = 0, and P c * = 1.43 (±0.10); cephalexin, J max * = 9.1 (±1.2), K m = 7.2 (±1.2), P m * = 0, and P c * = 1.30 (±0.10); cefatrizine, J max * = 0.73 (±0.19), K m = 0.58 (±0.17), P m * = 0.17 (±0.03), and P c * = 1.25 (±0.10); and cephradine, J max * = 1.57 (±0.84), K m = 1.48 (±0.75), P m * = 0.25 (±0.07), and P c * = 1.06 (±0.08). The colon absorption parameter for cefaclor is P m * = 0.36 (±0.06, where J max * (mM) is the maximal flux, K m (mM) is the Michaelis constant, P m * is the passive membrane permeability, and P c*is the carrier permeability. Aminocephalosporin perfusion results indicate that jejunal absorption in the rat occurs by a nonpassive process, with some of the compounds possessing a small but statistically significant passive component, while the colon permeability is low and follows a simple passive absorption mechanism.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015974920682
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  • 8
    Electronic Resource
    Electronic Resource
    Intestinal Absorption of Peptides and Peptide Analogues: Implications of Fasting Pancreatic Serine Protease Levels and pH on the Extent of Oral Absorption in Dogs and Humans (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 320-325 
    Details
    ISSN: 1573-904X
    Keywords: chymotrypsin ; dog ; human ; intestinal metabolism ; oral absorption ; pancreatic serine protease ; peptide ; peptide-like drugs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract In order to describe and predict the impact of intestinal metabolism on peptide absorption, intestinal chymotrypsin activity, flow rate, and pH were characterized in fasted, duodenally fistulated dogs as a function of gastrointestinal (GI) motility phase. GI motility was classified as either active or quiescent. Cumulative volume, F(t), and volumetric flow rate, Q(t), curves were constructed and the data were sorted according to motility phase. The mean ± SE active phase pH was 6.4 ± 0.3, whereas the quiescent phase pH was 7.3 ± 0.3. The difference between the mean active and the mean quiescent phase pH values was significant. The active and quiescent phase flow rates (ml/min) were also significantly different, at values of 1.2 ± 0.2 and 0.28 ± 0.07, respectively. The active phase flow rates were consistent among the dogs studied; however, the quiescent phase flow rates were highly variable among the dogs. The variability of the quiescent phase flow rates was expected since phase II of the GI motility cycle is characterized by intermediate, irregular spike activity. The mean active and quiescent phase chymotrypsin activities were 1.87 × 10-5 ± 0.53 × 10-5 and 1.56 × 10-5 ± 0.65 × 10-5 M, respectively. The active phase values were not statistically different among dogs, however, the quiescent phase values were found to be highly variable among dogs. The difference between the active and the quiescent phase chymotrypsin mean levels, however, was not statistically significant. The chymotrypsin levels determined in dogs were found to be approximately 10 times greater than those reported in humans. The significance of fasted-state chymotrypsin levels is discussed with respect to the impact of GI metabolism on peptide and peptide-like drug absorption in dogs. Further, given the intestinal metabolic differences between dogs and humans, the suitability of using the dog model for predicting the oral absorption of peptides in humans is discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015830600227
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  • 9
    Electronic Resource
    Electronic Resource
    Predicting Fraction Dose Absorbed in Humans Using a Macroscopic Mass Balance Approach (1991)
    Springer
    Pharmaceutical research 8 (1991), S. 979-988 
    Details
    ISSN: 1573-904X
    Keywords: extent of absorption ; macroscopic mass balance analysis ; mixing tank ; complete radial mixing model ; solubility ; oral drug absorption ; amoxicillin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A theoretical approach for estimating fraction dose absorbed in humans has been developed based on a macroscopic mass balance that incorporates membrane permeability and solubility considerations. The macroscopic mass balance approach (MMBA) is a flow model approach that utilizes fundamental mass transfer theory for estimating the extent of absorption for passively as well as nonpassively absorbed drugs. The mass balance on a tube with steady input and a wall flux of J w = P w C b results in the following expression for fraction dose absorbed, F: F = 2 An ∫0 1 C*b dz* where the absorption number, An = L/R · P w/v z 〉;, L and R are the intestinal length and radius, P w is the unbiased drug wall permeability, 〈v z 〉 is the axial fluid velocity, C*b = C b/Co and is the dimension-less bulk or lumen drug concentration, C b and C o are the bulk and initial drug concentrations, respectively, and z* is the fractional intestinal length and is equal to z/L. Three theoretical cases are considered: (I) C o ≤ S, C m ≤ S, (II) C o 〉 S, C m ≤ S, and (III) C o 〉 S, C m 〉 S, where S is the drug solubility and C m is the outlet drug concentration. Solving the general steady-state mass balance result for fraction dose absorbed using the mixing tank (MT) and complete radial mixing (CRM) models results in the expressions for the fraction dose absorbed in humans. Two previously published empirical correlations for estimating fraction dose absorbed in humans are discussed and shown to follow as special cases of this theoretical approach. The MMBA is also applied to amoxicillin, a commonly prescribed orally absorbed β-lactam antibiotic for several doses. The parameters used in the correlation were determined from in situ or in vitro experiments along with a calculated system scaling parameter. The fraction dose absorbed calculated using the MMBA is compared to human amoxicillin pharmacokinetic results from the literature with initial doses approximated to be both above and below its solubility. The results of the MMBA correlation are discussed with respect to the nonpassive absorption mechanism and solubility limitation of amoxicillin. The MMBA is shown to be a fundamental, theoretically based model for estimating fraction dose absorbed in humans from in situ and in vitro parameters from which previously published empirical correlations follow as special cases.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015892621261
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  • 10
    Electronic Resource
    Electronic Resource
    Estimating Human Oral Fraction Dose Absorbed: A Correlation Using Rat Intestinal Membrane Permeability for Passive and Carrier-Mediated Compounds (1988)
    Springer
    Pharmaceutical research 5 (1988), S. 651-654 
    Details
    ISSN: 1573-904X
    Keywords: carrier-mediated absorption ; film model ; fraction dose absorbed ; passive absorption ; permeability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Based on a simple tube model for drug absorption, the key parameters controlling drug absorption are shown to be the dimensionless effective permeability, P eff *, and the Graetz number, Gz, when metabolism or solubility/dissolution is not rate controlling. Estimating the Graetz number in humans and assuming that P aq * is not rate controlling gives the following equation for fraction dose absorbed: F = 1− e −2 P*w. The correlation between fraction dose absorbed in humans and P w * determined from steady-state perfused rat intestinal segments gives an excellent correlation. It is of particular significance that the correlation includes drugs that are absorbed by passive and carrier-mediated processes. This indicates that P w * is one of the key variables controlling oral drug absorption and that the correlation may be useful for estimating oral drug absorption in humans regardless of the mechanism of absorption.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015927004752
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