Intestinal drug absorption during induced net water absorption in man; a mechanistic study using antipyrine, atenolol and enalaprilat.

1. The effect of induced water absorption on the intestinal permeability of antipyrine, atenolol and enalaprilat in the proximal jejunum was studied in eight healthy subjects with a regional intestinal perfusion technique. 2. The mean (+/- s.d.) net water flux changed from a secretory status of 1.2 +/- 1.2 ml h-1 cm-1 to an absorptive status of -3.7 +/- 3.5 ml h-1 cm-1 (P < 0.0025) on the introduction of a hypo-osmolar glucose-containing electrolyte solution. 3. The mean permeability values for the three drugs in the eight subjects were unchanged despite the increase in net water absorption (5.7 +/- 3.0 to 7.0 +/- 3.6 x 10(-4) cm s-1 for antipyrine, 0.1 +/- 0.2 to 0.2 +/- 0.2 x 10(-4) cm s-1 for atenolol and 0.3 +/- 0.3 to 0.1 +/- 0.2 x 10(-4) cm s-1 for enalaprilat). One subject showed a large change in the permeability for antipyrine and atenolol in parallel with a large increase in water absorption, but enalaprilat was unaffected. 4. The luminal recovery of PEG 4000 was similar before (100 +/- 4%) and during (101 +/- 7%) induction of water absorption, which indicates that the barrier function of the intestine appears to be maintained during glucose-stimulated fluid absorption in man. 5. We conclude that induced net water absorption in man does not influence the paracellular permeability of hydrophilic drugs or drugs with high molecular weight to any significant extent.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of the contribution of the nasal cavity and gastrointestinal tract to drug absorption following nasal application to rats

Drugs applied to the nose in in vivo physiologic condition undergo absorption from the nasal cavity and the gastrointestinal (GI) tract because drug solution in the nasal cavity, together with mucus layer, is cleared to pharynx and then to the GI tract by coordinated beat of the cilia on nasal epithelial cells. The purpose of this study was to develop evaluate the contribution of the nasal cavity and the GI tract to drug absorption following nasal application and to clarify the relation to the transepithelial permeability of the drug (the permeability to Caco-2 monolayer, P(Caco-2)). Male Wistar rats received intravenous, nasal, and oral drug administration and drug concentration-time profiles in plasma were determined. Fractional absorption after nasal application (Fn) and oral administration (Fpo) were calculated from the area under the curve following intravenous injection (AUCiv), nasal application (AUCn), and oral administration (AUCpo) as AUCn/AUCiv and AUCpo/AUCiv, respectively. Fractional absorption from the nasal cavity (F(NC)) and the GI tract (F(GI)) following nasal application was calculated as (Fn-Fpo)/(1-Fpo) and Fpo(1-F(NC)), respectively. The shape of the curve between F(NC) and P(Caco-2) was similar with the one observed in the case of oral bioavailability except the curve shifted right. It is noteworthy that the relation between F(GI) and P(Caco-2) showed a bell-shaped curve with peak at 10(-6) cm/s of P(Caco-2). Highly permeable drug is primarily absorbed through the nasal mucosa before it is cleared to the GI tract. With the decrease in P(Caco-2), the larger amount of the drug is cleared to the GI tract and absorption from the GI tract is increased. Poorly permeable drug, on the other hand, was absorbed neither from the nasal was nor the GI tract. These findings suggest that the primary absorption site of drug after nasal application is decided by mucociliary clearance and absorption through the nasal mucosa.     

Establishment of Novel Prediction System of Intestinal Absorption in Humans Using Human Intestinal Tissues

The objective of this study was to establish a novel prediction system of drug absorption in humans by utilizing human intestinal tissues. Based on the transport index (TI), a newly defined parameter, calculated by taking account of the change in drug concentrations because of precipitation on the apical side and the amounts accumulated in the tissue and transported to the basal side, the absorbability of drugs in rank order as well as the fraction of dose absorbed (Fa) in humans were estimated. Human intestinal tissues taken from ulcerative colitis or Crohn’s disease patients were mounted in a mini-Ussing chamber and transport studies were performed to evaluate the permeation of drugs, including FD-4, a very low permeable marker, atenolol, a low permeable marker, and metoprolol, a high permeable marker. Although apparent permeability coefficients calculated by the conventional equation did not reflect human Fa values for FD-4, atenolol, and metoprolol, TI values were well correlated with Fa values, which are described by 100 ? [1 – e ^-f ?^{(TI – α)}]. Based on this equation, Fa values in humans for other test drugs were predicted successfully, indicating that our new system utilizing human intestinal tissues would be valuable for predicting oral drug absorption in humans. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2564–2571, 2013     

Determination of intraluminal theophylline concentrations after oral intake of an immediate- and a slow-release dosage form

The purpose of this study was to evaluate a protocol which enables determining luminal drug concentrations after oral drug administration in man. Human intestinal fluids were aspirated from two sampling sites (duodenum and jejunum) at different time points after oral intake of theophylline; an immediate- and a slow-release dosage form were used to demonstrate the feasibility of discriminating between different formulations. Osmolarity and pH of the aspirates were measured and theophylline concentrations were determined by HPLC-UV. After intake of the immediaterelease formulation of theophylline, duodenal maximum concentrations up to 3 mM were reached within 30 min. Theophylline appeared to be almost completely absorbed before it reached the second sampling site in the jejunum, as observed jejunal concentrations were lower than 10% of the maximal duodenal concentrations. These results are in agreement with fast dissolution and fast absorption through the intestinal mucosa, which could be expected as theophylline belongs to class I of the Biopharmaceutical Classification System. In contrast to the immediate-release formulation, administering the slow-release dosage form resulted in a gradual appearance of theophylline, reaching maximal intestinal concentrations below 300 muM. The proposed methodology can be used to assess luminal drug concentrations and to monitor the time- and site-dependent composition of intestinal fluids after intake of an oral dosage form. This approach may contribute to a better understanding of the behaviour of oral drug formulations in the gastrointestinal tract and may be exploited to further unravel the complexity of the gastrointestinal absorption process. In addition, knowledge of luminal drug concentrations may assist in the selection of drug concentrations applied in in-vitro permeability assays.     

Evolution of a detailed physiological model to simulate the gastrointestinal transit and absorption process in humans, part 1: oral solutions

To enable more precise prediction of oral drug absorption, an existing physiologically based absorption model was revised. The revised model reflects detailed knowledge of human gastrointestinal (GI) physiology including fluid secretion and absorption, and comprises an elaborate representation of the intestinal mucosa. The alimentary canal from the stomach to the rectum was divided into 12 compartments. A mucosal compartment was added to each luminal segment of the intestine. A training set of 111 passively absorbed drugs with reported fractions of dose absorbed was used to optimize the semiempirical equation, which calculates intestinal permeability coefficients. The model was subsequently integrated into an established physiologically based pharmacokinetic software and validated by prediction of plasma concentration-time profiles of eight test compounds with diverse physicochemical properties. A good correlation between the simulated and experimental fractions of dose absorbed was established for the 111 compounds in the training set. Subsequently, the concentration-time profiles of six out of eight test compounds were predicted with high accuracy. The detailed model for GI transit and absorption presented in this study can help to understand the complex processes of oral absorption better and will be useful during the drug development process.     

Comparison between active and passive drug transport in human intestinal epithelial (caco-2) cells in vitro and human jejunum in vivo

Drug transport rates in Caco-2 monolayers were compared with those obtained in the human jejunum in vivo. Permeability coefficients unbiased by the hydrodynamic conditions were calculated in order to allow direct comparison of the two models. The rapidly (passively) transported drugs naproxen, antipyrine and metoprolol had comparable permeability coefficients in Caco-2 cells and in human jejunum. The permeability coefficients of the slowly (passively) transported, hydrophilic drugs, terbutaline and atenolol, 79- and 27-fold lower, respectively, in Caco-2 cells than in jejunum. The carrier-mediated transport rates of L-dopa, L-leucine and D-glucose were also much slower in Caco-2 cells than in human jejunum. The lower permeability of the actively transported compounds and of atenolol and terbutaline is consistent with the colonic origin of the Caco-2 cells. The results indicate that Caco-2 monolayers can be used to predict passive drug transport in humans, while prediction of transport by carrier-mediated systems may require a scaling factor, due to a low expression of carriers in this cell line.     

Human small intestinal and colonic tissue mounted in the Ussing chamber as a tool for characterizing the intestinal absorption of drugs

The purpose of this study was to validate human small intestinal and colonic tissue mounted in the Ussing chamber as a tool for predicting the oral drug absorption in humans with the main focus on moderately and poorly permeable compounds. The obtained apparent permeability coefficient (P(app)) of eleven test compounds was compared to their fraction absorbed (Fa) in humans taken from the literature. Beside the conventional P(app) a new parameter, the apparent permeability coefficient total (P(app,total)), involving both the apical-to-basolateral permeability and the time-dependent compound accumulation in the tissue was established. The permeability of lucifer yellow (LY), a fluorescent marker of the paracellular pathway and the test compounds showed no obvious differences between small intestine and colon. Furthermore, small intestinal and colonic tissue from a single donor showed similar permeability of both LY and a transcellularly transported compound metoprolol. All test compounds including low molecular weight hydrophilic compounds such as metformin, atenolol, sulpiride and famotidine showed adequate permeability reflecting human Fa values (R(2)=0.87). The P(app) values of digoxin, a P-glycoprotein (P-gp) substrate, were not significantly affected by the addition of verapamil, a P-gp inhibitor. In contrast, the P(app,total) values of digoxin increased approximately threefold in the presence of verapamil. In conclusion, both small intestinal and colonic tissue mounted in the Ussing chamber provide a good opportunity to predict the oral drug absorption rate in humans even for moderately and poorly absorbed compounds. The novel calculation of P(app,total) allows the study of the carrier-mediated drug-drug interactions in human intestine.     

pH-dependent functional activity of P-glycoprotein in limiting intestinal absorption of protic drugs: kinetic analysis of quinidine efflux in situ

The purpose of this investigation is to evaluate the quantitative contribution of pH-dependent passive permeability on the functional activity of P-glycoprotein (P-gp) in limiting intestinal absorption of weakly basic drugs, in order to include this effect in prediction models. pH-dependent octanol/buffer partition coefficient, artificial membrane permeability and in situ rat intestinal permeability of quinidine were determined in the physiological pH range of gastrointestinal tract. In situ permeability, as a function of luminal pH, was also determined in the presence of P-gp inhibitor, verapamil (500 microM). Octanol/buffer partition coefficient, transport across artificial membrane, and rat in situ permeability showed high pH-dependency. Absorption quotient (AQ), calculated from in situ permeability to express the functional activity of P-gp, declined with increase in luminal pH or increase in luminal quinidine concentration because of the increased passive permeability or saturation of P-gp. AQ was 0.57 +/- 0.02 and 0.41 +/- 0.05, while passive permeability was 0.32 +/- 0.01 x 10(-4) cm/sec and 0.43 +/- 0.02 x 10(-4) cm/sec, in jejunum and ileum, respectively, at pH 7.4. Further, apparent Michaelis-Menten constants (K(M), J(P-gp,max)) for the quinidine efflux in jejunum indicated that efflux activity was more at luminal pH 4.5 over pH 7.4. K(M) values for jejunum quinidine efflux at pH 4.5 and pH 7.4 were determined to be 77.63 +/- 10.90 and 22.86 +/- 5.22 microM, with J(P-gp,max) values of 1.47 +/- 0.08 and 0.62 +/- 0.04 nM/cm2/sec, respectively. AQ vs passive permeability showed significant relationship indicating dependency of P-gp-mediated efflux on pH-dependent passive permeability, which is dictated by ionization status for a protic or ampholytic drug. In conclusion, an orally administered drug is absorbed from various segments of intestine, which inherit difference in luminal pH, transcellular permeability and P-gp expression. In situ data suggests that pH-dependency and regional variability in passive permeability of protic substrates significantly influence their P-gp-mediated efflux and may have implications on predictions of the in vivo drug absorption.     

Absorption of rivastigmine from different regions of the gastrointestinal tract in humans

The objective of this study was to evaluate the rate and extent of absorption and metabolism of rivastigmine (Exelon), ENA 713) after site-specific delivery of the drug in the gastrointestinal (GI) tract using a naso-intestinal intubation technique. Healthy adult subjects (n = 7) received, on four separate occasions, a 3-mg dose of a rivastigmine solution (2 mg/mL) orally and via a naso-intestinal tube to three GI sites (jejunum, ileum, and ascending colon). On each of the 3 treatment days for regional GI dosing, the tube was progressed to each of the three GI sites, which was determined by a radiographical technique prior to dosing. On the fourth day, following tube withdrawal, the subject received a 3-mg oral dose of a rivastigmine solution. Plasma samples were obtained at different multiple time points, and the plasma concentrations of rivastigmine and its metabolite, NAP 226-90, were determined using a gas chromatography/mass spectrometry (GC/MS) method. Rivastigmine was rapidly absorbed following both oral administration and site-specific delivery to different regions of the GI tract (jejunum, ileum, and ascending colon). Compared with oral administration (AUV(0- infinity ) = 21 ng*h/mL, C(max) = 12.8 ng/mL, and t(max) = 0.87 h), delivery of the drug directly into the ileum, jejunum, and ascending colon did not change the extent of absorption, but the time to peak concentration appeared to be smaller (mean t(max) ranged from 0.4-0.6 h, with no change in C(max)). The relative bioavailability of rivastigmine from all three regions of the GI tract was comparable to that following oral administration. The metabolite levels (AUC, C(max)) were also similar among the three different regions of the GI tract when compared to the oral dose. It was concluded that rivastigmine is rapidly and equally well absorbed following an oral dose and after specific delivery to different regions of the small intestine and ascending colon. GI metabolism of rivastigmine to its major metabolite, NAP 226-90, occurs to a similar extent in different segments of the GI tract.     

Oral absorption of 21-corticosteroid esters: a function of aqueous stability and intestinal enzyme activity and distribution

The intestinal absorption of hydrocortisone and prednisolone are compared with three water-soluble derivatives (succinate, phosphate, and lysinate) in experiments at two levels of biological system complexity. Rates of absorption are compared by measuring permeabilities from rat intestinal perfusions of drugs and derivatives in solution. Extents of absorption are compared over a 10-fold dose range of parent steroid and with the steroid derivatives by measuring plasma levels from solid oral dosage in dogs. While the parent steroids are well absorbed over the entire length of the intestinal tract, variability in plasma levels is observed at higher doses. Limited solubility and resultant dissolution rate variability are likely to be playing a role in the early erratic blood level profiles found at higher doses. While the soluble prodrugs have a dissolution rate advantage which results in a greater concentration gradient, their absorption is limited by their aqueous luminal stability, their polarity and resultant passive membrane permeability, and the distribution and activity of enzyme reconversion sites in the intestinal tract. The unstable lysinate ester, targeted for aminopeptidase, has an absorption profile and permeability similar to that of the parent steroid. The absorption of the moderately stable succinate ester is limited by its polarity and the activity of intestinal esterases. The stable phosphate derivative is well absorbed in the upper intestine, where high levels of alkaline phosphatase exist, while the prodrug polarity and drop-off of enzyme activity limit its absorption from the lower gastrointestinal (GI) tract.     

Absorption sites of orally administered drugs in the small intestine

Introduction: In pharmacotherapy, drugs are mostly taken orally to be absorbed systemically from the small intestine, and some drugs are known to have preferential absorption sites in the small intestine. It would therefore be valuable to know the absorption sites of orally administered drugs and the influencing factors.

Areas covered:In this review, the author summarizes the reported absorption sites of orally administered drugs, as well as, influencing factors and experimental techniques. Information on the main absorption sites and influencing factors can help to develop ideal drug delivery systems and more effective pharmacotherapies.

Expert opinion: Various factors including: the solubility, lipophilicity, luminal concentration, pKa value, transporter substrate specificity, transporter expression, luminal fluid pH, gastrointestinal transit time, and intestinal metabolism determine the site-dependent intestinal absorption. However, most of the dissolved fraction of orally administered drugs including substrates for ABC and SLC transporters, except for some weakly basic drugs with higher pKa values, are considered to be absorbed sequentially from the proximal small intestine. Securing the solubility and stability of drugs prior to reaching to the main absorption sites and appropriate delivery rates of drugs at absorption sites are important goals for achieving effective pharmacotherapy.     

重组水蛭素在大鼠胃肠道中的吸收

目的考察重组水蛭素-2(rHV2)经大鼠口服后在胃肠道中的吸收及分布。方法用HPLC、荧光检测及共聚焦扫描电镜对rHV2在大鼠体内的吸收和分布进行研究。结果大鼠给药后1 h在血浆中检测到rHV2原型成分。po 125I-rHV2后血浆中检测到三氯醋酸沉淀的放射活性,酶抑制剂能够提高其生物利用度。FITC-rHV2 po后3 h可见大鼠胃、肠道各部分荧光占给药的1.20%～27.68%,其中能被凝胶空柱排阻的占2.27%～38.75%。共聚焦扫描电镜揭示水蛭素在整个小肠段都有吸收,但是回肠段吸收相对较多。结论重组水蛭素-2可以部分地在肠腔内保持活性,并能够以活性形式被吸收。     

Pancreatoduodenectomy as a source of human small intestine for Ussing chamber investigations and comparative studies with rat tissue

A clear understanding of oral drug absorption is an important aspect of the drug development process. The permeability of drug compounds across intact sections of small intestine from numerous species, including man, has often been investigated using modified Ussing chambers. The maintenance of viable, intact tissue is critical to the success of this technique. This study therefore aimed to assess the viability and integrity of tissue from patients undergoing pancreatoduodenectomy, for use in cross-species Ussing chamber studies. Electrical parameters (potential difference, mV; short-circuit current, μA.cm(-2) ; resistance, Ω.cm(2) ) were monitored over the duration of each experiment, as was the permeability of the paracellular marker atenolol. The permeability values (Papp; cm/s × 10(-6) ) for a training-set of compounds, displaying a broad range of physicochemical properties and known human fraction absorbed values, were determined in both rat and human jejunum, as well as Caco-2 cell monolayers. The results indicate that human jejunum sourced from pancreatoduodenectomy remained viable and intact for the duration of experiments. Permeability values generated in rat and human jejunum correlate well (R(2) = 0.86), however the relationship between permeability in human tissue and Caco-2 cells was comparatively weak (R(2) = 0.58). Relating permeability to known human fraction absorbed (hFabs) values results in a remarkably similar relationship to both rat and human jejunum Papp values. It can be concluded that human jejunum sourced from pancreatoduodenectomy is a suitable source of tissue for Ussing chamber permeability investigations. The relationship between permeability and hFabs is comparable to results reported using alternative test compounds.     

Rapid in vivo dissolution of ketoprofen: implications on the biopharmaceutics classification system

The aim of this paper was to investigate the in vivo dissolution behavior of ketoprofen, a Class II drug according to the Biopharmaceutics Classification System (BCS), in the upper small intestine of dogs. An intubations method was used, where no blocking balloons were used to prevent luminal drug transport along the GI tract. Our design allowed the drug to be transported freely to more distal parts of the GI tract and also, it was supported by a pharmacokinetic study. Pharmacokinetic parameters of ketoprofen were determined in dogs after administering approximately 0.27 mg kg(-1) (solution) or approximately 1.47 mg kg(-1) (suspension) in oral bolus doses. There were not statistical significant differences in plasma concentrations for both formulations, either in the maximum concentrations C(max) or AUC following oral dose administration. The rapid disappearance of ketoprofen from the intestinal lumen, reflected by low mass recovery in the supernatant and sediment of the collected intestinal fluid samples, in comparison to that recovery of the non-absorbable marker phenol red, suggests that ketoprofen is emptying into the small intestine and is rapidly dissolved and absorbed. In this study, the in vivo results clearly show that the absorption rate of ketoprofen is not dissolution limited; therefore ketoprofen would be essentially equivalent to Class I drugs and could be considered for waiver of bioavailability and bioequivalence testing.     

A compartmental absorption and transit model for estimating oral drug absorption.

This report describes a compartmental absorption and transit model to estimate the fraction of dose absorbed and the rate of drug absorption for passively transported drugs in immediate release products. The model considers simultaneous small intestinal transit flow and drug absorption. Both analytical and numerical methods were utilized to solve the model equations. It was found that the fraction of dose absorbed can be estimated by F(a) = 1-(1+0.54 P(eff))(-7), where P(eff) is the human effective permeability in cm/h. A good correlation was found between the fraction of dose absorbed and the effective permeability for ten drugs covering a wide range of absorption characteristics. The model was able to explain the oral plasma concentration profiles of atenolol.     

An in vitro system for prediction of oral absorption of relatively water-soluble drugs and ester prodrugs

We developed an in vitro system simulating the physiological condition in the gastrointestinal (GI) tract for prediction of oral absorption of relatively water-soluble drugs and ester prodrug pivampicillin. This evaluation system includes a drug-dissolving vessel (DDV, assumed stomach), a pH adjustment vessel (PAV, assumed intestine) and a side-by-side diffusion chamber that is mounted by a Caco-2 monolayer, which is grown on a polycarbonate filter, or by a rat intestine between the donor and receiver compartments. Our proposed system can accommodate large amounts of solid drugs, simulating a drastic pH change process in GI tract, that is, an orally administered solid drug is dissolved in the stomach (pH 1-2) and transferred to the intestine (pH 6), and that dissolution process can also be monitored. The optimal flow rates for our system are 0.35-1.10 ml/min. Using this system, cumulative permeations of eight relatively water-soluble drugs were compared, and these cumulative permeations indicated the ability of drug absorption in humans. Drugs that permeated across a Caco-2 monolayer at cumulative permeation of more than 0.03% or over 0.04% in rat intestine can be almost completely absorbed in humans. If the cumulative permeation across a Caco-2 monolayer is lower than 0.03% or below 0.04% in the rat intestine, there was a good linear correlation between cumulative permeation across a Caco-2 monolayer and oral absorption in humans, or between cumulative permeation across a rat intestine and oral absorption in humans. In the case of relatively water-soluble drugs, a good linear correlation was obtained between cumulative permeation across a Caco-2 monolayer and cumulative permeation across a rat intestine. This result indicates that it is possible to predict the oral absorption of a relatively water-soluble drug in humans based on the cumulative permeation of the drug across a Caco-2 monolayer and/or a rat intestine. The time course of permeation of the ester prodrug pivampicillin, which is metabolized in a Caco-2 monolayer or in a rat intestine, was also evaluated. It stated clearly that it is also possible to predict the oral absorption of pivampicillin in humans based on the cumulative permeation across a Caco-2 monolayer or rat intestine. Our newly developed system enables more kinds of oral preparations and also pH-dependent soluble drugs to be evaluated.     

Mechanistic Fluid Transport Model to Estimate Gastrointestinal Fluid Volume and Its Dynamic Change Over Time

Gastrointestinal (GI) fluid volume and its dynamic change are integral to study drug disintegration, dissolution, transit, and absorption. However, key questions regarding the local volume and its absorption, secretion, and transit remain unanswered. The dynamic fluid compartment absorption and transit (DFCAT) model is proposed to estimate in vivo GI volume and GI fluid transport based on magnetic resonance imaging (MRI) quantified fluid volume. The model was validated using GI local concentration of phenol red in human GI tract, which was directly measured by human GI intubation study after oral dosing of non-absorbable phenol red. The measured local GI concentration of phenol red ranged from 0.05 to 168 μg/mL (stomach), to 563 μg/mL (duodenum), to 202 μg/mL (proximal jejunum), and to 478 μg/mL (distal jejunum). The DFCAT model characterized observed MRI fluid volume and its dynamic changes from 275 to 46.5 mL in stomach (from 0 to 30 min) with mucus layer volume of 40 mL. The volumes of the 30 small intestine compartments were characterized by a max of 14.98 mL to a min of 0.26 mL (0–120 min) and a mucus layer volume of 5 mL per compartment. Regional fluid volumes over 0 to 120 min ranged from 5.6 to 20.38 mL in the proximal small intestine, 36.4 to 44.08 mL in distal small intestine, and from 42 to 64.46 mL in total small intestine. The DFCAT model can be applied to predict drug dissolution and absorption in the human GI tract with future improvements.     

Intestinal permeability of forskolin by in situ single pass perfusion in rats

The intestinal permeability of forskolin was investigated using a single pass intestinal perfusion (SPIP) technique in rats. SPIP was performed in different intestinal segments (duodenum, jejunum, ileum, and colon) with three concentrations of forskolin (11.90, 29.75, and 59.90 μg/mL). The investigations of adsorption and stability were performed to ensure that the disappearance of forskolin from the perfusate was due to intestinal absorption. The results of the SPIP study indicated that forskolin could be absorbed in all segments of the intestine. The effective permeability (P (eff)) of forskolin was in the range of drugs with high intestinal permeability. The P (eff) was highest in the duodenum as compared to other intestinal segments. The decreases of P (eff) in the duodenum and ileum at the highest forskolin concentration suggested a saturable transport process. The addition of verapamil, a P-glycoprotein inhibitor, significantly enhanced the permeability of forskolin across the rat jejunum. The absorbed fraction of dissolved forskolin after oral administration in humans was estimated to be 100 % calculated from rat P (eff). In conclusion, dissolved forskolin can be absorbed readily in the intestine. The low aqueous solubility of forskolin might be a crucial factor for its poor oral bioavailability.     

Analysis and prediction of absorption profile including hepatic first-pass metabolism of N-methyltyramine, a potent stimulant of gastrin release present in beer, after oral ingestion in rats by gastrointestinal-transit-absorption model.

The prediction method for the plasma concentration-time profile of N-methyltyramine (NMT), a potent stimulant of gastrin release present in beer after oral ingestion in rats was examined using the previously developed Gastrointestinal (GI)-Transit-Absorption Model, with the addition of a process of hepatic first-pass metabolism. Phenol red was used as a nonabsorbable marker for estimation of the GI transit rate constant for eight segments in the GI tract. The first order absorption rate constant for each segment was estimated by means of a conventional in situ closed loop method. The results of in situ absorption experiments showed that NMT is well absorbed in the small intestine, especially in the duodenum and jejunum. Using the GI-Transit-Absorption Model, it was demonstrated that more than 90% of orally ingested NMT is absorbed in the small intestine, and that the substantial absorption site for NMT in vivo is the lower jejunum and the ileum. However, the observed bioavailability was only 39.0%. The in vitro metabolism study clarified that NMT is metabolized in the liver, but not in the small-intestinal mucosa. With the hepatic intrinsic clearance value (2.0 liters/h) calculated from the rate of metabolism in vitro, the hepatic availability was estimated to be 0.510 on the basis of a well stirred model, which was validated by two other methods to calculate the hepatic availability of NMT. The plasma concentration-time curve and bioavailability of NMT after oral ingestion were well predicted by the GI-Transit-Absorption Model with the hepatic first-pass metabolism process.     

Analysis and prediction of absorption behavior for theophylline orally administered as powders based on gastrointestinal-transit-absorption (Gita) model

Absorption behavior of theophylline, categorized into Class I of Biopharmaceutics Classification System, orally administered as powders in rats was analyzed and predicted by Gastrointestinal-Transit-Absorption (GITA) model, which was modified to describe GI-transit kinetics and dissolution of powders orally administered. First of all, GI-transit kinetics of glass beads was examined to describe the transit kinetics of powders through GI tract in rats. The results showed that the gastric emptying of glass beads was slower than that of solution, but that there was not much difference in the transit rate constants through the small intestine and cecum between glass beads and solution. Furthermore, to introduce the dissolution process of theophylline powders into GITA model, an in-vitro dissolution test was examined for theophylline powders according to the Japanese Pharmacopoeia paddle method. The dissolution rate constants calculated based on the mean dissolution time were not so different in the range of pH from 1.2 to 6.5. Using the parameters for GI transit, dissolution and absorption obtained, the plasma concentration-time profile of theophylline after oral administration as powders to rats was predicted based on GITA model. The profile calculated was significantly correlated with the observed time course of plasma concentration for theophylline, and the parameters such as C(max) and AUC based on the predicted curve coincided with those on the observed data, showing that GITA model is useful for the prediction of the absorption behavior of drugs administered as powders. The simulation studies showed that about 80% of orally administered theophylline powders dissolved in the stomach and that the remaining powders rapidly moved to the lower jejunum and ileum, where they dissolved. Furthermore, it was suggested that theophylline is absorbed mostly in the upper small intestine, duodenum, upper jejunum and lower jejunum, after its oral administration as powders.