Predicting Fraction Dose Absorbed in Humans Using a Macroscopic Mass Balance Approach

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/C_o 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 -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.     

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.     

Method to Estimate the Rate and Extent of Intestinal Absorption in Conscious Rats Using an Absorption Probe and Portal Blood Sampling

Purpose. A variety of methods exist which determine the rate and extent of intestinal absorption. The method described here employs an internal absorption reference probe and portal blood sampling in unanesthetized rat. Methods. Theophylline and tritiated water were selected as absorption reference probes since they are quantitatively absorbed in conscious rat. The fraction of an intestinal dose which reaches portal blood was determined from the resulting portal-systemic blood concentration gradients of the drug relative to the absorption probe. The absorption probes provide a means to calculate the drug mass reaching portal blood without the need of measuring the portal blood flow rate. The technique was evaluated with verapamil and a well-absorbed 5-lipoxygenase inhibitor, A-79035. Results. The fraction of an intrajejunal dose of A-79035 reaching the portal vein (F_G) was 0.86 using theophylline as the absorption probe. Verapamil, which is susceptible to extensive hepatic first-pass elimination, was completely absorbed (F_G = 0.98) within 1 hour, but was only 21.4% bioavailable. Absorption rate constants, estimated from initial appearance rates in portal blood, were used to monitor factors that affect drug absorption. For example, with a dose solution containing 30% PEG-400, the absorption rate constants of theophylline and A-79035 were significantly reduced. Anesthesia reduced the absorption rate constant for theophylline in rats by 40% compared to conscious animals. Conclusions. The technique detailed here allows reliable, direct measurement of intestinal absorption which may assist in characterizing oral dosing for novel therapeutic agents.     

Intestinal permeability and its relevance for absorption and elimination

Human jejunal permeability (P_eff) is determined in the intestinal region with the highest expression of carrier proteins and largest surface area. Intestinal P_eff are often based on multiple parallel transport processes. Site-specific jejunal P_eff cannot reflect the permeability along the intestinal tract, but they are useful for approximating the fraction oral dose absorbed. It seems like drugs with a jejunal P_eff > 1.5 x 10^–4 cm s^–1 will be completely absorbed no matter which transport mechanism(s) are utilized. Many drugs that are significantly effluxed in vitro have a rapid and complete intestinal absorption (i.e. >85%) mediated by passive transcellular diffusion. The determined jejunal P_eff for drugs transported mainly by absorptive carriers (such as peptide and amino acid transporters) will accurately predict the fraction of the dose absorbed as a consequence of the regional expression. The data also show that: (1) the human intestinal epithelium has a large resistance towards large and hydrophilic compounds; and (2) the paracellular route has a low contribution for compounds larger than approximately molecular weight 200. There is a need for more exploratory in vivo studies to clarify drug absorption and first-pass extraction along the intestine. One is encouraged to develop in vivo perfusion techniques for more distal parts of the gastrointestinal tract in humans. This would stimulate the development of more relevant and complex in vitro absorption models and form the basis for an accurate physiologically based pharmacokinetic modelling of oral drug absorption.     

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.     

LC-MS/MS法测定大鼠口服延胡索提取物后延胡索乙素和脱氢紫堇碱的药代动力学

建立检测大鼠血浆中延胡索乙素和脱氢紫堇碱分析方法，并应用有机溶剂沉淀法提取含药血浆中的生物碱类成分，色谱采用SB-C₁₈反相柱，流动相为乙腈-乙酸铵(0.1%乙酸)梯度洗脱，质谱采用多反应监测(MRM)方式进行正离子检测，用于定量分析的例子对分别为m/z 356.2→m/z 191.9(延胡索乙素)和m/z 366.2→m/z 350.2(脱氢紫堇碱)。测定血浆中这两种成分的线性范围均为1.0～1 000 ng·mL^{-1，定量下限为1.0 ng·mL-1，相关系数分别为0.994和0.992，延胡索乙素的回收率为71.71%～91.59%，脱氢紫堇碱的回收率为83.27%～103.15%，方法的精密度、准确度和稳定性均符合要求。结果显示，该法选择性强、灵敏度高、操作简便，适用于血浆延胡索乙素和脱氢紫堇碱的药代动力学研究。}     

The Relationship Between Rat Intestinal Permeability and Hydrophilic Probe Size

Purpose. The relationship between rat intestinal permeability (P_app) of a range of hydrophilic probe molecules and probe geometry was examined. Methods. Molecules studied included mannitol, the polyethylene glycols (PEGs) 400, 900, and 4000, the dextran conjugated dye Texas Red^® (MW 3000) and the polysaccharide inulin (MW 5500). Molecular surface area, volume and cross-sectional diameter for each probe were determined from computer models. The effect of the bile salt sodium cholate, and bile salt: fatty acid mixed micelles on probe intestinal permeability was also studied. Results. Of the size parameters tested, cross-sectional diameter correlated best with log intestinal permeability. The data was fitted to a relationship of the form P_app = P⁰ _app exp(–Kr_ca) where r_ca is the molecular cross sectional radius, P⁰ _app and K are constants. Estimates of equivalent pore radii (R) were also made; the use of r_ca giving the most reasonable estimate of R. Absorption of all probes was enhanced by both simple and mixed micellar systems. Conclusions. For large hydrophilic probes, and possibly protein drugs, cross sectional diameter is a more important size parameter than volume based values for evaluating size-related retarded absorption. The relationship established may be used as a tool to assess absorption enhancement potential of excipients.     

Effects of Pluronic F68 and Labrasol on the intestinal absorption and pharmacokinetics of rifampicin in rats

The aim of this study was to investigate the effects of Pluronic F68 and Labrasol on the intestinal absorption and pharmacokinetics of rifampicin. Intestinal permeability of rifampicin with or without excipients was evaluated by an in situ single-pass perfusion method. A highperformance liquid chromatographic method was applied to study the pharmacokinetics of rifampicin with or without excipients. Labrasol or Pluronic F68 (0.1% and 0.05%, v/v), co-perfused with rifampicin (60 μg/mL), significantly increased in situ permeability. Similarly, verapamil (a typical P-gp inhibitor) also increased in situ permeability, but to a lesser extent. In vivo, the oral administration of rifampicin with or without Pluronic F68, Labrasol or verapamil resulted in statistically significant effect on t_1/2 (4.83 to 7.75, 6.42 and 7.46 h) and total body clearance (0.46 to 0.26, 0.28, 0.24 L/h/kg). In addition, Pluronic F68, Labrasol and verapamil produced minor changes in AUC_0−t, which improved 1.55-, 1.54-, and 1.73-fold in comparison to control group, respectively. These results showed that Labrasol and Pluronic F68 might inhibit the function of P-gp in the intestine, thereby increasing intestinal absorption and changing the pharmacokinetic parameters of rifampicin. Therefore, excipient selection is an important factor to consider in rational formulation design.     

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.     

Transport Kinetics of Iron Chelators and Their Chelates in Caco-2 Cells

Purpose Caco-2 monolayers were used to contrast the bidirectional transport of iron chelators and their chelates and to estimate fundamental kinetics associated with their intestinal absorption. Methods Bidirectional transport was studied at 37°C and pH 7.4 using 500-μM concentrations. Monolayer integrity was tested via transepithelial electrical resistance and sodium fluorescein permeability. Apical and basolateral analysis provided mass balance evidence. Apparent permeability coefficient (P_app) served to rank and compare molecules and estimate in vivo bioavailability. Model-dependent rate constants defined cellular influx and efflux. Results 1) P_app ranked in decreasing order for chelators from directional transport studies were CP363 > deferiprone> ICL670 > CP502 > deferoxamine (DFO). 2) Fe(CP502)₃, Fe(ICL670)₂, and FeDFO were not measurable in receiving chambers, whereas Fe(deferiprone)₃ and Fe(CP363)₃ were detected in both directions. 3) CP363 was transported significantly faster from the basolateral to the apical direction than the converse. 4) Mass balance of donor and receiver chambers gave approximately 100% recovery in all cases. 5) Kinetic analysis supports the view that the Caco-2 chelator efflux constants are generally greater than their influx constants. Conclusions Caco-2 cells are useful in screening iron chelators and chelates and estimating bioavailabilities. Structure and distribution coefficients partially predict passive transport through Caco-2 monolayers.     

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.     

Effects of Structural Modifications on the Intestinal Permeability of Angiotensin II Receptor Antagonists and the Correlation of In Vitro,In Situ,and In Vivo Absorption

Purpose. The effects of structural modifications on the membrane permeability of angiotensin II (Ang II) receptor antagonists and the usefulness of in vitro and in situ intestinal absorption models in predicting in vivo absorption or bioavailability were investigated. Methods. Intestinal permeability was determined in vitro using Caco-2 cell monolayers and in situ using a perfused rat intestine method. Several physicochemical parameters were either measured or computed, and correlated with intestinal permeation. Results. Permeation coefficients (Pa) across Caco-2 cell monolayers correlated well with both in situ absorption rate constants (ka) and in vivo bioavailability or % absorption. For these Ang II antagonists, Pa values larger than 3 × 10^–6 cm sec^–1 and in situ ka values of 2 × 10^–4 min^–1 cm^–1 or above were associated with good in vivo absorption. Structural modifications at the R₅ position, where a COOH group was substituted with either a CHO or CH₂OH group, enhanced the permeability of the Ang II receptor antagonists up to 100-fold. There were good correlations between permeability and log P(octanol/buffer), log P_HPLCcharge, solvation/desolvation energy and assigned hydrogen bonding potential. Conclusions. The correlations obtained in this study indicate that both the Caco-2 cell model and the in situ perfused rat intestine could be used to predict intestinal absorption in vivo. Structural modifications of the Ang II antagonists had a significant impact on the intestinal permeability. Charge, solvation energy, and hydrogen bonding are predominant determinants of intestinal permeability and oral bioavailability of these compounds.     

Role of glucose transporters in the intestinal absorption of gastrodin,a highly water-soluble drug with good oral bioavailability

Abstract

Gastrodin, a sedative drug, is a highly water-soluble phenolic glucoside with poor liposolubility but exhibits good oral bioavailability. The current study aims to investigate whether glucose transporters (GLTs) are involved in the intestinal absorption of gastrodin. The intestinal absorption kinetics of gastrodin was determined using the rat everted gut sac model, the Caco-2 cell culture model and the perfused rat intestinal model. In vivo pharmacokinetic studies using diabetic rats with high GLT expression were performed. Saturable intestinal absorption of gastrodin was observed in rat everted gut sacs. The apparent permeability (Papp) of gastrodin from the apical (A) to basolateral (B) side in Caco-2 cells was two-fold higher than that from B to A. Glucose or phlorizin, a sodium-dependent GLT (SGLT) inhibitor, reduced the absorption rates of gastrodin from perfused rat intestines. In vivo pharmacokinetic studies showed that the time of maximum plasma gastrodin concentration (T_max) was prolonged from 28 to 72?min when orally co-administered with four times higher dose of glucose. However, the T_max of gastrodin in diabetic rats was significantly lowered to 20?min because of the high intestinal SGLT1 level. In conclusion, our findings indicate that SGLT1 can facilitate the intestinal absorption of gastrodin.     

A Correlation Between the Permeability Characteristics of a Series of Peptides Using an in Vitro Cell Culture Model (Caco-2) and Those Using an in Situ Perfused Rat Ileum Model of the Intestinal Mucosa

In an attempt to establish an in vitro/in situ correlation of intestinal permeability data, the permeability coefficients (P _app) for a series of model peptides, which were determined using an in situ perfused rat ileum model, were compared to the permeability coefficients (P _mono) determined using an in vitro cell culture model (Caco-2). The model peptides, which were all blocked on the N-terminal (acetyl, Ac) and the C-terminal (amide, NH2) ends, consisted of D-phenylalanine (F) residues (e.g., AcFNH₂, AcFFNH₂, AcFFFNH₂). To alter the degree of hydrogen bonding potential, the nitrogens of the amide bonds were sequentially methylated [e.g., AcFF(Me)FNH₂, AcF(Me)F(Me)FNH₂, Ac(Me)F(Me)F(Me)FNH₂, Ac-(Me)F(Me)F(Me)FNH(Me)]. These peptides were shown not to be metabolized in the in situ perfused rat ileum system. The results of the transport experiments showed that there were poor correlations between the apparent permeability coefficients (P _app) determined in an in situ perfused rat ileum model and the octanol–water partition coefficients (r = 0.60) or the hydrogen bonding numbers (r = 0.63) of these peptides. However, good correlations were observed between the in situ P _app values for these peptides and their partition coefficients in heptane–ethylene glycol (r = 0.96) and the differences in their partition coefficients between octanol–water and isooctane–water (r = 0.86). These results suggest that lipophilicity may not be the major factor in determining the intestinal permeability of these peptides and that hydrogen bonding potential may be a major contributing factor. A good correlation (r = 0.94) was also observed between the P _app values determined for these peptides in the in situ perfused ileum model and those P _mono values determined in the in vitro cell culture model (Caco-2) (Conradi et al., Pharm. Res. 8:1453–1460, 1991). These results suggest that the permeability values determined in the Caco-2 cell culture model may be a good predictor of the intestinal permeability of peptides.     

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 (P _w*), determined by single-pass perfusion, were also site dependent. P _w* 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.     

Quantitative analysis of cabozantinib in pharmaceutical dosage forms using green RP-HPTLC and green NP-HPTLC methods: A comparative evaluation

In this study, a novel antitumor drug cabozantinib (CZN) was estimated by a validated green reversed-phase high-performance thin-layer chromatography (RP-HPTLC) and normal-phase high-performance thin-layer chromatography (NP-HPTLC) techniques in the marketed tablets and capsules. The RP-HPTLC densitometry analysis of CZN was carried out using “RP-18 silica gel 60 F254S HPTLC plates”. Green acetone/water (85:15, v v^?1) combination was applied as the mobile phase for a RP-HPTLC-densitometry. However, green NP-HPTLC analysis of CZN was conducted using “NP-18 silica gel 60 F254S HPTLC plates”. Green ethyl acetate/ethanol (97.5:2.5, v v^?1) combination was applied for a green NP-HPLTC-densitometry. The detection of CZN was performed at λ_max = 247 nm for both of the techniques. The RP-HPTLC technique showed high sensitivity for the quantification of CZN in comparison to NP-HPTLC-densitometry. For a green RP-HPTLC-densitometry, the CZN content of marketed tablets and capsules were found to be 101.17% and 98.77%, respectively. However, for a green NP-HPTLC-densitometry, the CZN content of the marketed tablets and capsules were found to be 96.12% and 94.25%, respectively. Accordingly, the green RP-HPTLC technique was identified better than a green NP-HPTLC technique. Hence, the RP-HPTLC-densitometry can be successfully used for the quantification of CZN in pharmaceutical dosage forms containing CZN as one of the constituents.     

Intestinal permeability of mitragynine in rats using in situ absorption model

The intestinal permeability of mitragynine was investigated in situ using a single pass intestinal perfusion (SPIP) absorption model, in small intestine of rat using mitragynine in the absence/presence of the permeability markers, P-gp and/or CYP3A4 inhibitors. Mitragynine demonstrated high intestinal permeability (P_eff of 1.11 × 10^?4 cm/s) that is in the range of highly permeable drugs such as propranolol (P_eff of 1.27 × 10^?4 cm/s) indicating that it readily crosses the intestine. The addition of azithromycin (P-glycoprotein inhibitor) and ciprofloxacin (CYP3A4 inhibitor) or combination of both has no effect on intestinal permeability of mitragynine across the rat small intestine.     

Physiological mechanism-based analysis of dose-dependent gastrointestinal absorption of L-carnitine in rats

We evaluated the dose-dependent (saturable) gastrointestinal absorption of L -carnitine, a lipid-lowering agent, in rats by a physiological mechanism-based approach to clarify its absorption characteristics and to examine the in vitro (in situ)–in vivo correlation in intestinal transport. The intestinal absorption rate constant (k_a), which was estimated by the analysis of gastrointestinal disposition, decreased markedly from 0.1061 to 0.0042 min⁻¹ when the dose was increased from 0.05 μmol rat⁻¹ (low dose) to 100 μmol rat⁻¹ (high dose). The dose-dependence in k_a was attributable to the saturability of intestinal transport that, in the perfused intestine, was similar to the saturability in k_a. At the high dose, the apparent absorption rate constant (k_a′) of 0.0021 min⁻¹, which was estimated by the analysis of plasma concentrations after oral administration, was an order of magnitude smaller than the gastric emptying rate constant (k_g) of 0.059 min⁻¹ and comparable with the k_a of 0.0042 min⁻¹, suggesting that the gastrointestinal absorption of L -carnitine is absorption-limited in the intestine. At the low dose, where intestinal L -carnitine absorption was far more efficient, the k_a′ of 0.0172 min⁻¹ was smaller than the k_a of 0.1061 min⁻¹ and closer to the k_g of 0.072 min⁻¹, suggesting that apparent absorption was retarded by gastric emptying which is less efficient than intestinal absorption. This shift in the rate-determining process with an increase in dose explains the less marked dose dependence in k_a′ compared with k_a. The bioavailability decreased from 100 to 42% with an increase in dose. This could be accounted for quantitatively by a reduction in the fraction absorbed (F_a,oral) due to a reduction in k_a, assuming first-order absorption during the transit time of T_si through the small intestine (F_a,oral=1−exp(−k_a · T_si)). Thus, using L -carnitine as a model, this study has successfully demonstrated that the saturability in gastrointestinal absorption can be correlated with the intestinal transport in a quantitative and mechanism-based manner. This should be of help not only for developing more efficient oral L -carnitine delivery strategies, taking advantage of in vitro (in situ) information about the intestinal transport mechanism, but also for establishing a more generally applicable in vitro (in situ)–in vivo correlation in gastrointestinal absorption. © 1998 John Wiley & Sons, Ltd.