Local Absorption Kinetics of Levofloxacin from Intestinal Tract into Portal Vein in Conscious Rat Using Portal-Venous Concentration Difference

Purpose. The local absorption kinetics of levofloxacin from the intestinal tract was quantitatively evaluated by simultaneously measuring the portal and venous plasma concentrations in a conscious rat. Methods. The venous and upper portal blood vessels were cannulated through the jugular and pyloric veins, respectively. After oral or intravenous administration of levofloxacin, portal and venous concentrations of levofloxacin were simultaneously monitored. The absorption rate from the intestine into the portal system was calculated from the portal-venous difference in the plasma concentration of levofloxacin, considering the distribution of levofloxacin into erythrocytes. Portal blood flow rate was newly measured by an electromagnetic flow meter. Results. There was little portal-venous difference after an intravenous dose of levofloxacin. In contrast, after oral administration, the plasma concentration in the portal vein was constantly higher than that in the jugular vein, demonstrating that this difference was caused by the intestinal absorption of levofloxacin. Conclusions. Approximately 90% levofloxacin was absorbed as the intact form from the intestinal tract into the portal system. By considering the bioavailability of levofloxacin in rat, the hepatic extraction ratio in vivo of levofloxacin was estimated to be 30%. The mean local absorption time (t_a) was 1.44hr which coincided almost with the mean absorption time (MAT).     

A Heterogeneous Tube Model of Intestinal Drug Absorption Based on Probabilistic Concepts

Purpose. To develop an approach based on computer simulations for the study of intestinal drug absorption. Methods. The drug flow in the gastrointestinal tract was simulated with a biased random walk model in the heterogeneous tube model Pharm. Res. 16, 87-91, 1999), while probability concepts were used to describe the dissolution and absorption processes. An amount of drug was placed into the input end of the tube and allowed to flow, dissolve and absorb along the tube. Various drugs with a diversity in dissolution and permeability characteristics were considered. The fraction of dose absorbed (F _abs ) was monitored as a function of time measured in Monte Carlo steps (MCS). The absorption number An was calculated from the mean intestinal transit time and the absorption rate constant adhering to each of the drugs examined. Results. A correspondence between the probability factor used to simulate drug absorption and the conventional absorption rate constant derived from the analysis of data was established. For freely soluble drugs, the estimates for F _abs derived from simulations using as an intestinal transit time 24500 MCS (equivalent to 4.5 h) were in accord with the corresponding data obtained from literature. For sparingly soluble drugs, a comparison of the normalized concentration profiles in the tube derived from the heterogeneous tube model and the classical macroscopic mass balance approach enabled the estimation of the dissolution probability factor for five drugs examined. The prediction of F _abs can be accomplished using estimates for the absorption and the dissolution probability factors. Conclusions. A fully computerized approach which describes the flow, dissolution and absorption of drug in the gastrointestinal tract in terms of probability concepts was developed. This approach can be used to predict F _abs for drugs with various solubility and permeability characteristics provided that probability factors for dissolution and absorption are available.     

Short-period Double-dosing for Simultaneous Evaluation of Intestinal Absorption and Hepatic Disposition in a Single Conscious Rat Using Cephalexin as Test Drug

A new method has been developed for simultaneous evaluation of local absorption from the intestine into the portal system and local disposition through the liver, and for assessment of the bioavailability of a drug in a single conscious rat. The method is based on the difference between plasma concentrations in portal and systemic blood (PS method). Because cephalexin is known to be absorbed completely from the intestine and not to be eliminated through the liver, it was used as test drug to confirm the validity of the new method. The portal vein and the femoral artery of a rat were simultaneously cannulated and blood samples were obtained from both sites. Two methods of administration, single-dosing and double-dosing, were investigated and the efficacy of double-dosing (DD) was demonstrated. Rats received an intra-arterial (group A) or oral (group B) dose in single-dosing, whereas rats used for double-dosing received an oral dose 3 h after an intra-arterial dose (group C). After administration of cephalexin, the portal and arterial plasma concentrations were determined by HPLC. Groups A and B were monitored for 4 h and group C for 8 h. The portal-blood flow rate was measured by means of an electromagnetic flow-meter. Global and local moments were calculated by trapezoidal integration with extrapolation to infinite time. On the basis of the PS method, the local absorption ratio (F_a) and the mean local absorption time (t?_a) were estimated to be 0.975 ± 0.104 and 2.19 ± 0.51 h, respectively, in group B. By comparing the averaged moments between groups A and B, the extent of bioavailability (F), the mean absorption time (MAT) and the hepatic recovery ratio (F_H) were calculated to be 1.01, 1.92 h and 1.04, respectively. The mean hepatic transit time (t?_H) was negligible. In group C, F_a = 0.936 ± 0.107, t?_H = 1.55 ± 0.32 h, F = 1.08 ± 0.07, MAT = 1.55 ± 0.40 h and F_H = 1.17 ± 0.14 h, the mean values being close to those from groups A and B. In conclusion, the PS method with short-period double-dosing (PS-DD method) can offer an effective means of evaluating the local absorption kinetics of drugs, because F, MAT and F_H are obtained from a single conscious rat, and consequently the standard deviations of the quantities can be quickly estimated.     

Evaluation of Intestinal Absorption into the Portal System in Enterohepatic Circulation by Measuring the Difference in Portal–Venous Blood Concentrations of Diclofenac

Purpose. We evaluated the first-pass effects in vivo by the intestine and liver during enterohepatic circulation (EHC) by simultaneously measuring the portal and venous plasma concentrations of the rat. Methods. The venous and upper portal blood vessels were cannulated through the jugular and the pyloric veins, respectively, to obtain simultaneously blood samples from both sites. After diclofenac was injected as a bolus through the jugular vein, the concentrations of diclofenac in the portal and jugular veins were measured at time intervals. The absorption rate from the intestinal tract into the portal system was determined using the portal–venous difference in plasma concentrations of diclofenac, considering 40% partitioning of diclofenac into erythrocytes. Results. After one hour, the plasma concentration in the portal vein was always higher than that in the jugular vein in awakening rats with intact EHC (portal–venous blood concentration difference). No portal–venous difference was observed in awakening rats with bile-duct cannulation. Therefore, it was concluded that this portal–venous concentration difference was not due to the hepatic clearance but to diclofenac reabsorption from the intestinal tract. Conclusions. Appropriately 40% of the dose of diclofenac was reabsorbed over 8 hours from the intestinal tract into the portal system. By comparing the reabsorbed amounts in the portal system and in the systemic circulation, the hepatic extraction ratio in vivo (F_H) of diclofenac was estimated to be 63%.     

Pharmacokinetic Model to Describe the Lymphatic Absorption of r-metHu-Leptin After Subcutaneous Injection to Sheep

Purpose. The purpose of this work was to develop a pharmacokinetic model to describe the contribution of the lymphatics to the absorption and bioavailability of r-metHu-Leptin administered by subcutaneous (SC) injection to sheep. Methods. r-metHu-Leptin was administered either by bolus intravenous injection (0.1 mg/kg) into the jugular vein or by SC injection (0.15 mg/kg) into the interdigital space of the hind leg. The SC groups included a non-cannulated control group and a lymph-cannulated group, in which peripheral lymph was continuously collected from a cannula in the efferent popliteal lymph duct. Serum and lymph concentrations were determined by enzyme-linked immunosorbent assay and profiles were modeled using compartmental pharmacokinetic methods. The fraction of the dose reaching the systemic circulation (F _sys) and the proportions of the absorbed dose taken up via the blood (F _blood) and lymph (F _lymph) were determined. Results. Serum and lymph concentration vs. time profiles were well described by a two compartment model with parallel first order absorption into blood and lymph. F _sys for the SC control group was 60.4 ± 8.4%. In the lymph-cannulated group, 21.7 ± 6.4% of the dose was recovered in serum and 34.4 ± 9.7% was recovered in peripheral lymph giving a total fraction absorbed (F _abs) of 56.0 ± 10.3%. F _sys for the SC control group was not significantly different to F _abs in the lymph-cannulated group. Conclusion. This study has shown that the lymph represents the predominant pathway for absorption of r-metHu-Leptin after SC administration.     

Theoretical Considerations on Two Equations for Estimating the Extent of Absorption After Oral Administration of Drugs

Purpose. The amount of drug absorbed into portal blood after oral dosing (D_p.o,g) has been estimated using Ficks principle (Q-method), i.e., D_p.o,g = Q_h · (AUC_p.o,g – AUC_p.o,c), where Q_h is the portal blood flow rate, and AUC_p.o,g and AUC_p.o,c are the areas under the concentration-time curves of portal vein and systemic blood after oral dosing, respectively. However, this method may underestimate D_p.o,g, when the drug is subject to systemic intestinal elimination. An alternate equation (CL-method; D_p.o,g = CL_S · AUC_p.o,g) is described using a simple pharmacokinetic model, to estimate D_p.o,g in the presence of systemic intestinal elimination, where CL_S is systemic clearance. Methods. The model is composed of central, intestine and liver compartments, assuming that drug is eliminated by intestinal and/or hepatic pathways only. A comparison of both methods for estimating D_p.o,g was made using computer-simulation or experimental data of phenacetin from the literature. Results. The simulation study demonstrated that the Q-method underestimated D_p.o,g in the presence of significant intrinsic intestinal clearance, compared to the CL-method,. The similar results were observed using the experimental data of phenacetin. Conclusions. The CL-method can provide a better estimate of D_p.o,g, while the Q-method may underestimate D_p.o,g, when there is significant systemic intestinal elimination of drugs after oral administration. In addition, useful information for understanding the relationship between the extent of absorption and the first-pass effect by intestine and/or liver after oral dosing of drugs can be obtained from the present approach.     

Estimating Human Oral Fraction Dose Absorbed: A Correlation Using Rat Intestinal Membrane Permeability for Passive and Carrier-Mediated Compounds

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.     

Evaluation of Capacity-Limited First-Pass Effect through Liver by Three-Points Sampling in Portal and Hepatic Veins and Systemic Artery

Purpose. The three-points method was newly developed by sampling the portal and hepatic veins and systemic artery. A model of hepatic local disposition with the Michaelis-Menten elimination was proposed to explain the concentration dependency of the hepatic recovery ratio (F _H). Methods. 5-fluorouracil (5-FU) was selected as a model drug. 5-FU was administered orally 90 min after its intraarterial dose. Blood specimens in both femoral artery and hepatic vein were sampled after intraarterial dose, and blood specimens in both femoral artery and portal vein were taken after oral administration. Results. It was shown that F _H increased with an increase in the input drug concentration into the liver. The mean absorption time (MAT) estimated by nonlinear analysis agreed with the mean local absorption time (t _a) whereas MAT by linear analysis was significantly smaller than t _a. Conclusions. The three-points method was newly developed, and the proposed nonlinear model explained well the capacity-limited elimination of 5-FU through the liver. MAT by the nonlinear analysis was in good agreement with t _a.     

Comparison of Oral Absorption and Bioavailability of Drugs Between Monkey and Human

Purpose. To compare the oral absorption and bioavailability of numerous drugs with a wide variety of physicochemical and pharmacological properties between humans and monkeys and to explore potential reasons for the findings. Methods. Data for fraction of dose absorbed (F _a) and oral absolute bioavailability (F) were obtained by an extensive Medline database search. Inclusion and exclusion criteria were the same as those reported in our previous studies. A total of 43 and 35 drugs were selected for F _a and F comparison, respectively. The time to reach peak concentration (t _max), total clearance, and nonrenal clearance were evaluated for 15, 28, and 13 drugs, respectively. Results. F _a values in monkeys were similar or identical to those in humans. Additionally, similar t _max values were seen in monkeys and humans at comparable doses, thus indicating comparable absorption kinetics between the two species. Conversely, F values in monkeys were generally lower with coumarin being a marked exception. Both total and nonrenal clearances were evaluated and found to be generally greater in monkeys, supporting a generally higher first-pass metabolism and lower F in this species. This was also supported by published data suggesting greater in vitro hepatic drug metabolism for monkeys as compared to humans. Conclusions. Monkeys appear to be a good predictor of F _a in humans. However, a generally lower F makes monkeys a potentially poor predictor of human F. Higher reported metabolic clearances and hepatic enzyme activities in monkeys may account for this observation.     

Predicting Oral Absorption of Drugs: A Case Study with a Novel Class of Antimicrobial Agents

Purpose. The purpose of this work was to evaluate an oral absorption prediction model, maximum absorbable dose (MAD), which predicts a theoretical dose of drug that could be absorbed across rat intestine based on consideration of intestinal permeability, solute solubility, intestinal volume, and residence time. Methods. In the present study, Caco-2 cell permeability, as a surrogate for rat intestinal permeability, and aqueous solubility were measured for 27 oxazolidinones. The oxazolidinones are a novel class of potential antibacterial agents currently under investigation. These values were used to estimate MAD for each of the compounds. Finally, these predicted values were compared to previously measured bioavailability data in the rat in order to estimate oral absorption properties. Results. A reasonably good correlation between predicted dose absorbed and bioavailability was observed for most of the compounds. In a few cases involving relatively insoluble compounds, absorption was underestimated. For these compounds while aqueous solubility was low, solubility in 5% polysorbate 80 was significantly higher, a solvent possibly more representative of the small intestinal lumen. Conclusions. These results suggest that MAD may be useful for prioritizing early discovery candidates with respect to oral absorption potential. In the case of compounds with poor aqueous solubility, additional factors may have to be considered such as solubility in the intestinal lumen.     

Guidance in the Setting of Drug Particle Size Specifications to Minimize Variability in Absorption

Purpose. To provide guidance in setting particle size specifications for poorly soluble drugs to minimize variability in absorption. Methods. A previously reported computer method was used to simulate the percent of dose absorbed as a function of solubility, absorption rate constant, dose, and particle size. Results. The simulated percent of dose absorbed was tabulated over a realistic range of solubilities, absorption rate constants, and doses using drug particle sizes that might be typically found in a dosage form. Conclusions. The greatest effect of particle size on absorption was simulated for low dose- low solubility drugs. In general, the sensitivity of absorption to particle size decreased with increasing dose or solubility. At a solubility of 1 mg/mL, particle size had practically no effect on the percent of dose absorbed over the range of doses simulated (1–250 mg).     

An Integrated Model for Determining Causes of Poor Oral Drug Absorption

Purpose. To develop an integrated absorption model for estimating the fraction of dose absorbed and determining the causes of poor oral drug absorption. Methods. Both analytical and numerical methods were used to estimate the fraction of dose absorbed. Results. An integrated absorption model was developed by considering transit flow, dissolution, and permeation processes, simultaneously. A framework was proposed to determine permeability-, dissolution-, and solubility-limited absorption. Digoxin, griseofulvin, and panadiplon were employed to illustrate the applications of the integrated model in identifying the causes of poor absorption and guiding formulation development. Conclusions. The integrated absorption model was successfully applied to digoxin, griseofulvin, and panadiplon to estimate the fraction dose absorbed and to roughly determine the causes of poor oral drug absorption.     

Impact of Regional Intestinal pH Modulation on Absorption of Peptide Drugs: Oral Absorption Studies of Salmon Calcitonin in Beagle Dogs

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 (t_pH,min) and time to reach the peak plasma concentration (t_conc,max) of sCT (t_conc,max = 0.95 × t_pH,min + 14.1, n = 11, r² = 0.91). Plasma C_max 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.     

Mass Balance Approaches for Estimating the Intestinal Absorption and Metabolism of Peptides and Analogues: Theoretical Development and Applications

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 -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.     

Lipid Microemulsions for Improving Drug Dissolution and Oral Absorption: Physical and Biopharmaceutical Aspects

Purpose. This review highlights the state-of-the-art in pharmaceutical microemulsions with emphasis on self-emulsifying systems, from both a physical and biopharmaceutical perspective. Although these systems have several pharmaceutical applications, this review is primarily focused on their potential for oral drug delivery and intestinal absorption improvement. Methods. Physicochemical characteristics and formulation design based on drug solubility and membrane permeability are discussed. Results. Case studies in which lipid microemulsions have successfully been used to improve drug solubilization/dissolution and/or intestinal absorption of poorly absorbed drugs/peptides are presented. Conclusions. Drug development issues such as commercial viability, mechanisms involved, range of applicability, safety, scale-up and manufacture are outlined, and future research and development efforts to address these issues are discussed.     

Human Drug Absorption Kinetics and Comparison to Caco-2 Monolayer Permeabilities

Purpose. This study aims to assess the drug absorption kinetics of three drugs and compare their resulting first-order intestinal permeation rate constants to their Caco-2 monolayer permeabilities. Methods. In vitro dissolution — in vivo absorption analysis was conducted on four formulations of each ranitidine HC1, metoprolol tartrate, and piroxicam to yield apparent and "true human clinical permeation rate constants. Drug permeability coefficients through Caco-2 monolayers were also determined. Results. In vitro dissolution — in vivo absorption analysis revealed different relative and absolute contributions of dissolution and intestinal permeation to overall drug absorption kinetics for various drug formulations and yielded estimates of each drug's true and apparent human intestinal permeation rate constant [k _p = 0.225 hr^–1, 0.609 hr^–l, and 9.00 hr^–1 for ranitidine, metoprolol, and piroxicam, respectively]. A rank order relationship was observed for both the apparent and true permeation rate constant with Caco-2 monolayer permeability. The decrease in the true permeation rate constant relative to the apparent permeation rate constant was most significant (almost three-fold) for the least permeable compound, ranitidine. Conclusions. There were marked differences in the permeation kinetics of ranitidine, metoprolol, and piroxicam. The possibility of an association between absorption kinetics from dosage forms in humans and Caco-2 monolayer permeability may allow for a direct kinetic interpretation of human oral absorption from Caco-2 monolayer permeability values.     

Development and Validation of a Physiology-based Model for the Prediction of Oral Absorption in Monkeys

Purpose The development and validation of a physiology-based absorption model for orally administered drugs in monkeys is described. Materials and Methods Physiological parameters affecting intestinal transit and absorption of an orally administered drug in monkeys have been collected from the literature and implemented in a physiological model for passive absorption previously developed for rats and humans. Predicted fractions of dose absorbed have been compared to experimentally observed values for a set of N = 37 chemically diverse drugs. A sensitivity analysis was performed to assess the influence of various physiological model parameters on the predicted fraction dose absorbed. Results A Pearson’s correlation coefficient of 0.94 (95% confidence interval: [0.88, 0.97]; p < 0.0001) between the predicted and observed fraction dose absorbed in monkeys was obtained for compounds undergoing non-solubility limited passive absorption (N = 29). The sensitivity analysis revealed that the predictions of fractions dose absorbed in monkeys are very sensitive with respect to inter-individual variations of the small intestinal transit time. Conclusions The model is well suited to predict the fraction dose absorbed of passively absorbed compounds after oral administration and to assess the influence of inter-individual physiological variability on oral absorption in monkeys.     

Oral Absorption of FK506 in Rats

The oral absorption of FK506 in solid dispersion formulation was studied in rats. The obtained area under the concentration versus time curve (AUC) increased in a nonlinear fashion with a small dose-dependent increase in the peak blood concentrations (C _max). The peak concentration time (T _max) was observed within 30 min after administration in all dosing groups (1–10 mg/kg) with or without feeding, whereas the oral absorption of FK506 was reduced to about 50% by gavage at a dose of 1 mg/kg. Participation of first-pass elimination was suggested by comparing the blood levels after infusion via the portal vein with those after infusion via the femoral vein. Further, in an in vitro stability study and an in situ loop absorption study, FK506 was fairly stable in the gastrointestinal juice and was absorbed predominantly from the upper part of the small intestine.     

A Saturable Transport Mechanism in the Intestinal Absorption of Gabapentin Is the Underlying Cause of the Lack of Proportionality Between Increasing Dose and Drug Levels in Plasma

Gabapentin (l-(aminomethyl)cyclohexaneacetic acid) is a neuroprotective agent with antiepileptic properties. The structure is small (molecular weight less than 200), is zwitterionic, and resembles an amino acid with the exception that it does not contain a chiral carbon and the amino group is not alpha to the carboxylate functionality. Gabapentin is not metabolized by humans, and thus, the amount of gabapentin excreted by the renal route represents the fraction of dose absorbed. Clinical trials have reported dose-dependent bioavailabilities ranging from 73.8 ± 18.3 to 35.7 ± 18.3% when the dose was increased from 100 to 1600 mg. The permeability of gabapentin in the rat intestinal perfusion system was consistent with carrier-mediated absorption, i.e., a 75 to 80% decrease in permeability when the drug concentration was increased from 0.01 to 50 mM (0.46 ± 0.05 to 0.12 ± 0.04). Excellent agreement was obtained between the actual clinical values and the predicted values from in situ results for the fraction of dose absorbed calculated using the theoretically derived correlation, F _abs = 1 - exp(–2P _eff) by Ami-don et al. (Pharm. Res. 5:651–654, 1988). The permeability values obtained for gabapentin correspond to 67.4 and 30.2% of the dose absorbed at the low and high concentrations, respectively. In the everted rat intestinal ring system, gabapentin shared an inhibition profile similar to that of L-phenylalanine. Characteristics of gabapentin uptake included cross-inhibition with L-Phe, sensitivity to inhibition by L-Leu, stereoselectivity as evidenced by incomplete inhibition by D-Phe, and lack of effect by Gly. Our findings support absorption of gabapentin by a saturable pathway, system L, shared by the large hydrophobic amino acids, L-Phe and L-Leu. The saturable absorption pathway makes a major contribution to the lack of proportionality in plasma levels of drug with increasing dose ob-served in the clinic.     

In Vivo Absorption of Theophylline and Salicylic Acid from Rat Small Intestine

Abstract: In vivo absorption of theophylline and salicylic acid from the rat small intestine was studied by a closed segment technique. The drugs were administered at 1 and 4 mM in dissolved form, both in the presence and absence of phlorizin (0.01 mM). Drug concentrations were measured by high-pressure liquid chromatography. Phlorizin inhibited the absorption of theophylline (pK_a = 8.6) at 4 mM but not at 1 mM. In contrast, the absorption of salicylic acid (pK_a = 3) both at I and 4 mM was unaffected by phlorizin. This suggests that an active transport system, sensitive to phlorizin, is involved in the rat intestinal absorption of theophylline, but not in that of salicylic acid. Apart from differences in drug structure, differences in the degree of ionization may influence the access of acidic drugs to this transport system.