Mitomycin C radical cation studied by pulse radiolysis

The formation of the radical cation of mitomycin C (MMC.+) was investigated in aqueous solution by a pulse radiolysis method using SO4.- species as one electron oxidizing agent. The spectroscopic and kinetic characteristics of MMC.+ transients were determined, namely: absorption maxima at 295, 400 and 500 nm, the corresponding molar extinction coefficients are [symbol: see text] 295 = 5.63 x 10(3) dm3 mol-1 cm-1, [symbol: see text] 400 = 2.9 x 10(3) dm3 mol-1 cm-1, [symbol: see text] 500 = 2.32 x 10(3) dm3 mol-1 cm-1; the rate constant for formation of MMC.+ is k = (1.2 +/- 0.2) x 10(10) dm3 mol-1 s-1 and for decay 2k = (4.6 +/- 0.4) x 10(8) dm-3 mol-1 s-1. Based on this fact it can be assumed that not only the well-known mitomycin C radical anion (semiquinone, MMC.-) is efficiently involved in the radiotherapy process, but in a given oxidation environment the MMC.+ species could also play a role in this respect.     

In vitro and in situ absorption of etamsylate. Part 2: In vitro and in situ properties.

The oil to water partition behaviour, the diffusion across artificial lipid barriers and the in situ gastro-intestinal absorption of the haemostatic etamsylate were studied. Very small partition coefficients were obtained (0.015-0.13) which are independent on the pH (range 1 to 6) and the nature of the organic phase (n-hexane, n-octanol, ethylacetate). Using the Sartorius membrane stimulator small diffusion constants were calculated both at phase I pH 6.0 (kd = 7.82.10(-3)cm.min-1) and especially at phase I pH 1.2 (kd = 4.7.10(-6) cm x min-1). The in situ absorption experiments on male Wistar rats showed very poor gastric absorption, but considerable intestinal absorption rate (absorption rate constant ka = 0.39 +/- 0.19 h-1, absorption half life t1/2(ka) = 1.94 +/- 0.60 h). The ion-pair diffusion across the intestinal wall seems to be the main reason responsible for the fast intestinal absorption. The obtained results are consistent to the literature data concerning etamsylate pharmacokinetics in vivo.     

Effects of freezing on human skin permeability

The percutaneous absorption of water was measured in-vitro at 30 degrees C for pale caucasian abdominal skin which had been stored at -20 degrees C for up to 466 days and compared with fresh skin. Prolonged freezing of the skin did not affect the absorption of water which had a mean permeability coefficient of 1.71 +/- 0.62 X 10(-3) cm h-1 (180 diffusion experiments with 39 skin specimens). No significant difference was found between the absorption of water through human skin which was fresh or had been frozen. The mean permeability coefficient for skin which had not been frozen was 1.30 +/- 0.55 X 10(-3) cm h-1 for 6 skin specimens.     

Efficacy of a standard United Kingdom oral rehydration solution (ORS) and a hypotonic ORS assessed by human intestinal perfusion

Human triple-lumen intestinal perfusion was used to compare water and solute absorption from the oral rehydration solution (ORS) most widely used in the United Kingdom and a new experimental hypotonic ORS (HYPO-ORS). HYPO-ORS (osmolality 210 mOsm/kg) promoted significantly greater water absorption than UK-ORS (7.03 +/- 1.1 vs 2.73 +/- 1.0 ml cm-1 h-1; P less than 0.01). HYPO-ORS produced net sodium and chloride absorption whereas the low sodium UK-ORS produced a net secretion of these ions. Bicarbonate absorption was also greater from HYPO-ORS although potassium and glucose absorption were similar from both solutions. This study suggests that UK-ORS may not promote optimal water and solute absorption and that clinical studies with HYPO-ORS are indicated.     

Site of drug absorption after oral administration: assessment of membrane permeability and luminal concentration of drugs in each segment of gastrointestinal tract.

This study was conducted to assess the site of drug absorption in the gastrointestinal (GI) tract after oral administration. Drug permeability to different regions of rat intestine, jejunum, ileum and colon, was measured by in situ single-pass perfusion method. It was revealed that the epithelial surface area should not be a determinant of the regional difference in the intestinal permeability of highly permeable drugs. Effects of the mucus layer at the surface of the epithelium and the fluidity of the epithelial cell membrane on the drug permeability were investigated. These factors are demonstrated to contribute to the regional differences in intestinal drug permeability. The luminal drug concentration in each segment of the GI tract after oral administration was measured directly in fasted rats. Water ingested orally was absorbed quickly in the jejunum and the luminal fluid volume was diminished in the middle to lower part of the small intestine. According to the absorption of water luminal concentration of atenolol, a drug with low permeability, was elevated and exceeded the initial dose concentration. In contrast, the concentration of highly permeable drugs, antipyrine and metoprolol, decreased quickly in the upper part of the intestine and a significant amount of drugs was not detected in the lower jejunum and the ileum. From the time-profiles of luminal drug concentration, fraction of dose absorbed from each segment of the GI tract was calculated. Both antipyrine and metoprolol were found to be absorbed quickly at the upper part of the small intestine. In addition, the possible contribution of gastric absorption was demonstrated for these drugs. The pattern of site-dependent absorption of atenolol showed the higher absorbability in the middle and lower portion of the jejunum. These informations on site-dependent absorption of drugs are considered to be important for effective oral delivery systems.     

The short term effects of propranolol, atenolol and labetalol on antipyrine kinetics in normal subjects.

1 The effects of three day courses of propranolol 40 mg three times daily, atenolol 100 mg twice daily and labetalol 100 mg three times daily on antipyrine kinetics were examined in 13 normal subjects. 2 The mean antipyrine clearance initially was 41.3 +/- 12.4 ml/min (mean +/- s.d.) and fell to 35.0 +/- 12.1 ml/min following propranolol (P less than 0.025), 34.5 +/- 9.5 ml/min following atenolol (P less than 0.01), and 35.2 +/- 8.6 ml/min following labetalol (P less than 0.05). 3 The prolongation in antipyrine half-life was significant only following atenolol. Propranolol only caused a significant reduction in the volume of distribution of antipyrine. 4 These adrenoceptor antagonists appear to decrease antipyrine clearance in normal subjects. The reduction in antipyrine clearance was similar with all three drugs and appeared to be independent of the differing lipid solubilities and pharmacological profiles of the adrenoceptor antagonists examined.     

The influence of plasma binding on absorption/exsorption in the Caco-2 model of human intestinal absorption.

The Caco-2 cell monolayer has become an increasingly useful in-vitro model of human intestinal absorption. In this study we have determined the effect of plasma on the basolateral side on the absorption as well as exsorption of several drugs that are highly bound to plasma proteins. The drugs used included propranolol and quercetin, which both use the transcellular route of absorption, and taxol and oestradiol 17 beta-D-glucuronide, which are thought to undergo efflux by P-glycoprotein and the multidrug resistance protein MRP, respectively. All experiments were carried out under sink conditions to mimic normal absorption. It was necessary to use heparin anticoagulation for generation of the plasma, as EDTA was found to make the monolayers very leaky. The apparent permeability (P(app)) values for absorption were 1.54 x 10(-6) cm s(-1) for oestradiol 17 beta-D-glucuronide, 3.33 x 10(-6) cm s(-1) for taxol, 20.8 x 10(-6) cm s (-1) for quercetin, and 35.3 x 10(-6) cm s(-1) for propranolol. For these four compounds, plasma on the basolateral side had no influence on absorption. However, plasma on the basolateral side significantly reduced the efflux of oestradiol 17 beta-D-glucuronide by 66%, taxol by 75%, propranolol by 82%, and quercetin by 94%. Failure to consider the effect of plasma binding can result in an overestimate of basolateral to apical efflux and result in misleading net flux calculations.     

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.     

Cardiorespiratory effects of continuous i.v. administration of the ACE inhibitor enalaprilat in the critically ill.

1. Cardiorespiratory effects of long-term, continuous i.v. administration of the ACE inhibitor enalaprilat were studied. 2. Forty-five consecutive critically patients suffering from trauma or postoperative complications were randomly separated into three groups (15 patients in each group) receiving either 0.25 mg h-1 or 0.50 mg h-1 enalaprilat, respectively, or saline solution as placebo (= control group). The infusion was continued for 5 days. 3. Haemodynamic and respiratory parameters were intensively monitored on admission to the intensive care unit (= 'baseline' values) and daily during the next 5 days. 4. Mean arterial blood pressure (MAP) decreased significantly only in the enalaprilat-treated patients, whereas heart rate (HR) remained unchanged in these patients. 5. Pulmonary capillary wedge pressure (PCWP) and pulmonary artery pressure (PAP) were decreased by enalaprilat (0.50 mg h-1: PAP (mean +/- s.d.) decreased from 28.0 +/- 4.1 to 24.0 +/- 3.0 mm Hg) and remained significantly lower than in the control group. In the untreated control group, cardiac index (CI), oxygen consumption (VO2I) and oxygen delivery (DO2I) significantly decreased, which was blunted by enalaprilat infusion. Oxygen extraction (O2-extr) increased in both enalaprilat groups (0.25 mg h-1: from 26.1 +/- 5.5 to 30.4 +/- 4.0%; 0.50 mg h-1: 25.2 +/- 5.6 to 30.9 +/- 4.4%) and decreased in the control patients. 6. Right ventricular haemodynamics improved by enalaprilat infusion (0.50 mg h-1: RVEF increased from 40.0 +/- 3.5 to 45.5 +/- 4.0%). Lactate plasma concentrations decreased in the group with 0.50 mg h-1 enalaprilat (from 1.9 +/- 1.0 to 1.3 +/- 0.3 mg dl-1) and increased in the control patients. 7. Continuous infusion of the ACE inhibitor enalaprilat exerted beneficial cardiorespiratory effects in the critically ill. The widespread common risk of altered perfusion with decreased CI, DO2, VO2, O2-extr and increased lactate concentration was blunted by enalaprilat infusion. 8. Although 0.5 mg h-1 enalaprilat was most effective, a dose of 0.25 mg h-1 also showed beneficial haemodynamic effects in the critically ill.     

Epithelial transport of drugs in cell culture. II: Effect of extracellular calcium concentration on the paracellular transport of drugs of different lipophilicities across monolayers of intestinal epithelial (Caco-2) cells

A human intestinal cell line, Caco-2, was used as a model to study the passive diffusion of a homologous series of drugs (beta-blocking agents) of different lipophilicity across intestinal epithelium. The permeability of the Caco-2 monolayers was modulated by the use of a calcium switch assay. The transmembrane resistance could be reversibly decreased from approximately 280 ohms.cm2 (a resistance similar to that of colon epithelium) to approximately 60 ohms.cm2 (a resistance similar to that of small intestine epithelium). Transmission electron microscopy showed that the increased electrical permeability was caused by a reversible separation of the components of the junctional complex and not by cell detachment. In general, the increased paracellular permeability resulted in a 2- to 9-fold increase in the apparent permeability coefficients for the more hydrophilic drugs (e.g., from 0.20 +/- 0.010 x 10(-6) to 1.43 +/- 0.185 x 10(-6) cm/s for atenolol), while the transport parameters for the more lipophilic drugs remained unchanged (e.g., 43.03 +/- 3.64 x 10(-6) and 46.10 +/- 3.25 x 10(-6) cm/s for propranolol). These findings indicate that it is possible to study the contribution of the paracellular pathway to the transport of drugs in the Caco-2 model.     

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.     

Effect of intestinal fluid flux on ibuprofen absorption in the rat intestine

Previously the apparent permeability coefficient (P(app)) of ibuprofen was observed to vary depending on the perfusion medium employed. The present work explores the possible contributions to these differences. Studies were undertaken using an in situ single pass rat gut technique. Lumenal drug concentrations and plasma drug levels were assayed by HPLC. Absorption rate constants (k(0)) were determined from fractions of drug unabsorbed from the intestineat steady state. Plasma data were fitted to a two compartment open model with zero-order input. Significant differences in net fluid flux were observed between the various buffered perfusion media, with fluxes varying from -0.044+/-0.006 ml min(-1) to +0.057+/-0.013 ml min(-1), the lower and negative values occurring for lower pH media and the larger positive values tending to occur with media of higher pH. A linear relationship was found between the P(app) of ibuprofen and net water flux (y=1.13+11.3x; r(2)=0.80). Apparent zero-order rate constants for ibuprofen appearance in plasma correlated well with absorption rate constants estimated from steady state lumenal drug concentration [k(0(gut))]. From the linear relationship between P(app) and fluid flux a normalized P(app) for ibuprofen (i.e. the P(app) in the absence of net fluid flux) of 1.1 x 10(-4)cms(-1) was determined Net lumenal fluid flux is dependent on perfusion medium composition and significantly alters ibuprofen absorption. The differences observed for P(app) were reflected in systemic drug absorption concentrations. The findings of these studies underline the importance of standardizing the osmolarity of experimental media used for the determination of intestinal permeability data.     

A comparative in vitro study of transdermal absorption of a series of calcium channel antagonists.

The in vitro transdermal absorption of five calcium channel antagonists (nifedipine, nitrendipine, nicardipine, felodipine, and nimodipine) was studied using the skin of hairless rats as a membrane. The aim of this study was to determine the penetration parameters [permeability constant (Kp), lag time (T1, and flux (J)] as measures of the intrinsic transdermal permeabilities of these drugs, in order to predict the potential capacity of these drugs to be formulated in a therapeutical transdermal system (TTS). Reliable prediction of Kp values, using K'w (extrapolated capacity factor in 100% water) and P (n-octanol-water partition coefficient) values as independent variables in the parabolic, bilinear, and hyperbolic functions, were assayed. Nicardipine showed a higher mean transdermal penetration (Kp; 4.9 x 10(-3) cm.h-1) value than the other dihydropyridines. Nifedipine showed the shortest mean T1 value (5.1 h). The permeability rate constants of the calcium channel antagonists assayed can be predicted from their n-octanol-water partition coefficients, using the parabolic function (r = 0.984, p less than 0.01). Nicardipine would be the most suitable candidate for formulation in a TTS design.     

Effects of glycerides on the intestinal absorption of cyclosporine a using the in-situ mesenteric vein cannulated rat model

The purpose of this study was to evaluate and compare the effect of glycerides with different fatty acid distributions (e.g. Arlacel 186, Capmul GMO and Captex 350) on Cyclosporine absorption in rat ileum segment using the modified single-pass intestinal perfusion with mesenteric vein cannulation. Drug concentration in the perfusate and blood plasma was analyzed by HPLC; and permeability coefficients were calculated from drug appearance in blood (P(blood)) and disappearance from perfusate (P(lumen)). Particle size was measured using Malvern Zetasaizer 1000HSA. Rheologic properties were measured using Brookfield viscometer. The results show that the average particle sizes after dilution (100 folds) of formulae containing Arlacel 186, Capmul GMO and Captex 350 and containing 0.8 mM CsA were 260+/-35.8, 130+/-11.4 and 37.5+/-6.0 nm, respectively. The polydispersity index was 0.6, 0.7 and 0.108 for formulations with Arlacel 186, Capmul GMO and Captex 350, respectively. CsA permeability coefficients (P(blood)) calculated from drug appearance in the blood in presence of Arlacel 186, Capmul GMO and Captex 350 were 0.3x10(-6), 1.0x10(-6) and 1.7x10(-6) cm2/sec, respectively. Phenol red was used as a water marker to determine net water absorption and secretion. Its constant concentration suggested that formulation did not alter intestinal water flux. From the results we can conclude that degree of glyceride esterification has a potential impact on the average particle size distribution and polydispersity of the formed micelles on dilution, which on turn contribute to the interaction between membrane and drug.     

Quinidine disposition in relation to antipyrine elimination and debrisoquine phenotype in alcoholic patients with and without cirrhosis

Single dose disposition of oral quinidine (400 mg sulfate) was studied in a control group of subjects (No. = 6) and in hospitalized alcoholic patients involving one group with (No. = 6) and one group without (No. = 11) hepatic cirrhosis. All subjects also underwent an antipyrine and a debrisoquine test. Patients with cirrhosis had a prolonged elimination half-life (29.5 +/- 5.9 h) and low clearance (24 +/- 7 ml.kg-1.h-1) of antipyrine and also a considerably higher debrisoquine metabolic ratio (18.8 +/- 3.3) than the controls, whereas the alcoholics without cirrhosis had metabolic patterns for these two test compounds comparable to those seen in the controls (antipyrine half-life: 8.8 +/- 1.1 h and 9.8 +/- 2.0 h; debrisoquine metabolic ratio: 3.6 +/- 0.7 and 3.8 +/- 1.2 for alcoholics and controls respectively). In patients with cirrhosis the apparent elimination half-life of quinidine was longer (12.8 +/- 1.8 h) whereas after oral administration clearance of quinidine (15.6 +/- 3.5 l.h-1) and quinidine/3-hydroxyquinidine ratio (9.9 +/- 2.1) were not different from controls (quinidine clearance: 13.45 +/- 1.9 l.h-1; quinidine/3-hydroxyquinidine: 10.3 +/- 2.7). A possible change in distribution patterns of quinidine in cirrhotics may explain these findings.     

The pharmacokinetics of mefloquine in man: lack of effect of mefloquine on antipyrine metabolism.

A method is described for the determination of the new antimalarial agent, mefloquine, in plasma and urine. After oral administration of 750 mg mefloquine to six volunteers, absorption, was apparently slow, with plasma mefloquine concentrations at 24 h (559 +/- 181 ng ml-1; mean +/- s.d.) higher than at 6 h (459 +/- 166 ng ml-1). The elimination half-life was 373 +/- 249 h, oral clearance was 5.09 +/- 2.7 1 h-1, and apparent volume of distribution was 35.7 +/- 30.7 l kg-1 (assuming 100% bioavailability). Mefloquine (750 mg) had no significant effect on salivary kinetics of antipyrine or on the metabolic clearance of antipyrine to its three main metabolites, 3-hydroxymethylantipyrine, 4-hydroxyantipyrine and norantipyrine, when antipyrine was administered either 2 h or 2 weeks after dosing with mefloquine.     

The influence of caprate on rectal absorption of phenoxymethylpenicillin: experience from an in-vivo perfusion in humans

The aim of this in-vivo perfusion study in humans was to investigate the influence of a penetration enhancer, sodium caprate, on the rectal absorption of phenoxymethylpenicillin and antipyrine. Six subjects, 3 male and 3 female, were included in two separate studies using perfusion solution of different pH (T1 and T2, respectively). Each in-vivo rectal perfusion investigation lasted for 200 min and consisted of two periods of 100 min, the first serving as a control, and sodium caprate being added in the second period in both T1 and T2. The concentrations of phenoxymethylpenicillin, antipyrine and sodium caprate in the outlet perfusate were assayed by HPLC, as was the plasma concentrations of phenoxymethylpenicillin. At pH 6.0 (0-100 min) the fraction absorbed (f(abs)) and effective permeability (P(eff)) of phenoxymethylpenicillin were 0.3% and 0.06 x 4 cm s(-1), respectively, and remained unaffected by the addition of sodium caprate. When the same subjects were perfused at pH 7.4, the f(abs) and P(eff) of phenoxymethylpenicillin were 2.4% and 0.11 x 10(-4) cm s(-1) (0-100 min), respectively, also remaining unchanged by addition of sodium caprate (100-200 min). It was possible to determine the plasma AUC of phenoxymethylpenicillin after addition of sodium caprate in three subjects at both pHs; this was in the range of 14.0-62.8 and 56.4-231 (min micromol L(-1)) at pH 6.0 and 7.4, respectively. Interestingly, there was a correlation between P(eff) for sodium caprate and the individual plasma AUC and C(max) of phenoxymethyl-penicillin, which indicates that the permeability of the enhancer in the tissue upon which it should act is crucial for achieving an effect. The f(abs) and the P(eff) of antipyrine were not affected at either pH when sodium caprate was added to the perfusion solution. In conclusion, the plasma pharmacokinetics of phenoxymethylpenicillin suggested a slightly increased rectal absorption at pH 7.4 in subjects where sodium caprate was transported into the rectal tissue. However, the increased P(eff) for phenoxymethylpenicillin wastoo small to detectfrom the outlet perfusate, which suggests that sodium caprate alone has a limited effect on the permeability in-vivo across the rectal epithelium when it is presented in a solution.     

Link between drug absorption solubility and permeability measurements in Caco-2 cells

The objective of this investigation was to establish a relationship between drug permeability and solubility in vitro and the extent of drug absorption in humans. We selected drugs with varying permeabilities and solubilities with the aim of establishing a relationship between permeability and solubility measurements in vitro and the extent of absorption in vivo. Effective permeability coefficients of the model drugs (naproxen, phenytoin, propranolol, diltiazem, salicylic acid, ephedrine, cimetidine, chlorothiazide, and furosemide) at 37 degrees C and pH 7.2 were estimated using the Caco-2 cell line. Saturation solubilities of the model drugs were estimated at pH 7.2 and at 37 degrees C. Data obtained from the permeability and solubility experiments were employed in classifying the drugs into high and low permeability-solubility groups. The permeability coefficients ranged from 1x10(-7) to 4x10(-5) cm/s, and a good correlation was observed between the permeability coefficients in Caco-2 cells and percent absorbed in humans. Drugs in the high permeability, high solubility class are completely absorbed (90% or higher). The study results indicate that there is a strong link between permeability measured in Caco-2 cells, solubility, and fraction of drug absorbed in humans.     

Biopharmaceutics classification of selected beta-blockers: solubility and permeability class membership

The purpose of this study was to determine the permeability and solubility of seven beta-blockers (acebutolol, atenolol, labetalol, metoprolol, nadolol, sotalol, and timolol) and to classify them according to the Biopharmaceutics Classification System (BCS). Apparent permeability coefficients (Papp) were measured using the Caco-2 cell line, and the solubility was determined at 37 degrees C over a pH range of 1.0-7.5. The permeability coefficients ranged from 1.0x10(-7) to 4.8x10(-5) cm/s. On the basis of the in vitro permeability and solubility data observed in the study, labetolol, metoprolol, and timolol can be categorized as BCS Class I drugs, whereas acebutolol, atenolol, and nadolol belong to BCS Class III. The permeability coefficients in Caco-2 cells were consistent with the reported extent of intestinal absorption in humans for all drugs except sotalol. Sotalol displayed low permeability in the Caco-2 cell line, but the extent of intestinal absorption in humans is over 90%. The low permeability through the Caco-2 monolayers might be largely related to its low lipophilicity. In addition, the difference between the tightness of the intercellular junction in vivo and in vitro may partially contribute to this disparity in the sotalol permeability of in vivo and in vitro.