Human in Vivo Regional Intestinal Permeability: Importance for

Review pubs.acs.org/molecularpharmaceutics

Human in Vivo Regional Intestinal Permeability: Importance for Pharmaceutical Drug Development Hans Lennernas̈ Department of Pharmaceutics, Uppsala University, 753 12 Uppsala, Sweden ABSTRACT: Both the development and regulation of pharmaceutical dosage forms have undergone significant improvements and development over the past 25 years, due primarily to the extensive application of the biopharmaceutical classification system (BCS). The Biopharmaceutics Drug Disposition Classification System, which was published in 2005, has also been a useful resource for predicting the influence of transporters in several pharmacokinetic processes. However, there remains a need for the pharmaceutical industry to develop reliable in vitro/in vivo correlations and in silico methods for predicting the rate and extent of complex gastrointestinal (GI) absorption, the bioavailability, and the plasma concentration−time curves for orally administered drug products. Accordingly, a more rational approach is required, one in which high quality in vitro or in silico characterizations of active pharmaceutical ingredients and formulations are integrated into physiologically based in silico biopharmaceutics models to capture the full complexity of GI drug absorption. The need for better understanding of the in vivo GI process has recently become evident after an unsuccessful attempt to predict the GI absorption of BCS class II and IV drugs. Reliable data on the in vivo permeability of the human intestine (Peff) from various intestinal regions is recognized as one of the key biopharmaceutical requirements when developing in silico GI biopharmaceutics models with improved predictive accuracy. The Peff values for human jejunum and ileum, based on historical open, single-pass, perfusion studies are presented in this review. The main objective of this review is to summarize and discuss the relevance and current status of these human in vivo regional intestinal permeability values. KEYWORDS: human intestinal permeability, drug absorption, bioavailability, Biopharmaceutics Classification System, Biopharmaceutics Drug Disposition Classification System, intestinal transporters, pharmacokinetics, intestinal perfusion

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INTRODUCTION

pharmaceutical products (http://www.imi.europa.eu/content/ orbito). BCS classifies all drugs into four classes: Class 1 (high solubility, high permeability), Class 2 (low solubility, high permeability), Class 3 (high solubility, low permeability), and Class 4 (low solubility, low permeability). In 2005, the Biopharmaceutics Drug Disposition Classification System (BDDCS) was developed and began to demonstrate its usefulness in predicting the influence of membrane transport proteins on several biopharmaceutic and pharmacokinetic (PK) processes (such as drug disposition and potential drug−drug interactions in the intestine and/or liver).6 Based on the research on transporter−enzyme interplay from several in vitro and in vivo studies, the BDDCS classifies drug substances into four classes based on aqueous solubility and extent of metabolism: Class 1 (high solubility, extensive metabolism), Class 2 (low solubility, extensive metabolism), Class 3 (high solubility, poor metabolism), and Class 4 (low solubility, poor metabolism). An extensive BDDCS classification for more than

The investigation, outcome prediction, development, and regulation of oral pharmaceutical dosage forms have undergone profound development over the past 25 years, due primarily to the widespread use of the Biopharmaceutical Classification System (BCS). 1 The BCS and the Food and Drug Administration (FDA) scale-up and postapproval changes (SUPAC) guidelines were developed during the 1990s and became public later in that decade. Both these guidelines and the current concepts underlying the BCS have assisted pharmaceutical scientists in pharmaceutical research and development. The BCS has had and still has a direct regulatory and industrial impact.2−5 Ongoing efforts to intensively combine in silico modeling and simulation with the design and evaluation of any experimental work may further contribute to the progress of pharmaceutical scientists in industry and academia and in their interaction with regulatory authorities, by reducing time, effort, and costs as a result of reducing the number of in vivo bioequivalence studies needed. For example, the IMI project OrBiTo (oral biopharmaceutics tools) is a panEuropean research consortium, which aims to develop novel experimental and theoretical simulation tools (in silico) to be used in the research, development, and regulation of oral © 2013 American Chemical Society

Received: Revised: Accepted: Published: 12

June 10, 2013 November 3, 2013 November 8, 2013 November 8, 2013 dx.doi.org/10.1021/mp4003392 | Mol. Pharmaceutics 2014, 11, 12−23

Molecular Pharmaceutics

Review

900 drugs has been reported.7 The role of the extent of metabolism as an alternative to the intestinal permeability and fraction of the dose absorbed (fa) in the classification system has also been under discussion recently.8 The BCS and BDDCS are central concepts, along with in silico modeling and simulation, in the evolution of biopharmaceutical, bioequivalence, and PK concepts as applied to drug research and development and regulatory advice and decision processes.9,10 The human gastrointestinal (GI) system of course has several crucial functions besides the absorption and secretion of drugs and their metabolites. It absorbs nutrients and fluids in parallel with its function as an efficient barrier against potentially hazardous bacteria and ingested and locally formed toxins. Accordingly, the single intestinal epithelial layer (which is composed mainly of enterocytes and colonocytes) and the gutassociated lymphoid tissue (the largest immunological tissue in the body) regulate the balance between efficient nutrient and fluid absorption and optimal protection against toxins.11 The successful design and development of oral pharmaceutical products requires in-depth knowledge of the relevant biopharmaceutical and PK properties of the active pharmaceutical ingredient (API) and the pharmaceutical excipients in the dosage form. To obtain pharmacological efficacy and a successful clinical outcome, an oral pharmaceutical product should deliver the drug at a certain rate, thus ensuring that a predetermined plasma concentration−time profile is achieved for the active drug(s). The main biopharmaceutical parameters involved in the successful oral delivery of an API include its physical, chemical, and biological properties, the design and composition of the pharmaceutical formulation, and the absorption conditions at different physiological sites along the intestine. It is well-known that the transepithelial permeability of the small and large intestine varies with the intestinal site for drugs transported by passive diffusion and/or carrier-mediated mechanisms.5,12,13 Understanding the regional differences in luminal conditions, GI transit and permeability is a fundamental requirement for establishing the subject-by-formulation interaction concept (which takes intersubject variations into consideration in relation to dosage form performance). This concept is expected to have a major impact on bioequivalence assessment, generic development strategies, and the exchangeability of different generic drug products in the future. There are several recent published reviews that discuss the role of membrane transport proteins in pharmacodynamics (PD) and PK.14−17 The primary focus of this report is to discuss the onset of absorption, the in vivo effective permeability of the human jejunum (Peff), and aspects of in vivo estimations of regional intestinal Peff in humans. Oral Administration of DrugsThe Roles of Stomach and Intestine in Absorption. The gastric emptying process controls the onset of drug absorption following oral drug administration.18−21 Absorption from the stomach is minor compared to the intestine because of the gastric epithelial barrier preventing diffusion, the relatively small available surface area, and the negligible expression of nutrient (uptake) transport proteins.22 Even lipophilic and weakly acidic drugs (acid dissociation constant, pKa, of about 7−8) such as phenobarbiturate and pentobarbiturate are absorbed 15−20 times more rapidly in the rat proximal small intestine than in the stomach.23 The absorption of basic drugs from the stomach is even lower than that of uncharged dissolved acidic drugs. For a compound to be able to be absorbed in the stomach it needs to have high acidic solubility, rapid dissolution, often

uncharged, and a very high gastric permeability. As a consequence stomach absorption is minimal for the vast majority of drugs even though it has been shown for salicylic acid.24 The therapeutic outcome after administration of a drug with limited gastric absorption, a high jejunal Peff, and a short terminal half-life (1.5 h) can be illustrated by the experience with L-dopa.25−27 In Parkinson’s patients, the clinical outcome was significantly improved when a duodenal infusion was prescribed instead of tablets.28−30 This continuous infusion system avoids the problems of the highly variable and sometimes delayed gastric emptying by delivering the L-dopa into the proximal small intestine where the intestinal permeability, mediated through an amino acid transporter, is high. This approach significantly reduced fluctuations in the plasma concentration−time profile and provided a more stable PD response in patients with advanced Parkinson’s disease.28−30 Gastric emptying is influenced by a large number of factors, possibly including circadian rhythm.19−21,31−33 For example, the maximum concentration (Cmax) of L-dopa in plasma was reduced, and the time to Cmax (Tmax) was delayed in Parkinson’s patients when the oral dose (tablet) was taken in the evening or in the supine position during the day in comparison with a morning oral dose (Figure 1).34 However,

Figure 1. Effect of circadian rhythmicity on L-dopa pharmacokinetics (PK) in patients with Parkinson’s disease. L-dopa was absorbed more slowly during the night, probably as a result of delayed gastric emptying. However, the extent of absorption and the bioavailability were both unaffected. Since the oral plasma pharmacokinetic parameters were less affected by posture than by nighttime dosing, this study suggests that circadian rhythms have a pronounced effect on gastric emptying and absorption rate. Nevertheless, body position may also be an important factor, and it is recommended that L-dopa tablets are taken in an upright position that is sustained for at least 30 min.34

the bioavailability of L-dopa was, as expected, the same for bedtime, supine day-time, and morning dosing, as the fa of L-dopa given with a decarboxylase inhibitor is >95%.26 This is one example that demonstrates the much higher epithelial Peff in the proximal small intestine than in the stomach mucosal barrier. Human in Vivo Jejunal Peff and Its Relevance for Drug Absorption. Clinical investigation of intestinal permeability in vivo in humans is limited, especially if direct measurements of specific transport mechanisms are the objective. Three main methods have been used to investigate intestinal permeability: (a) regional intestinal single-pass perfusion; (b) oral ingestion and collection of urinary marker molecules to represent 13

dx.doi.org/10.1021/mp4003392 | Mol. Pharmaceutics 2014, 11, 12−23


Review

different physicochemical properties and transport mechanisms; (c) approximation of the permeability from plasma PK data. Direct measurement of the effective intestinal permeability (Peff), of drugs and their transport mechanism(s) in humans is possible using regional intestinal perfusion techniques. In general, four clinical tools have been employed in the small intestine and rectum for this purpose: (i) a triple-lumen tube with a mixing segment, (ii) a multilumen tube with a proximal occluding balloon, (iii) a multilumen tube (Loc-I-Gut or Loc-ICol) with two balloons occluding a 10 cm intestinal segment, and (iv) isolation of two adjacent 20 cm jejunal segments using a multilumen perfusion catheter. The advantages and disadvantages of the various intestinal perfusion techniques have been discussed elsewhere.35−46 Direct determinations of in vivo Peff in humans have been carried out using a single-pass perfusion technique in the proximal jejunum (Loc-I-Gut) for 30 drugs and in the rectum (Loc-I-Col) for two drugs and two other compounds.45−52 These perfusion studies were carried out in healthy male and female subjects without the use of any systemically administered anesthesia; the instructions for these procedures have been described in detail elsewhere.38,45,52−54 The cylindrical area representing the jejunal segment (2πrL) was calculated using the intestinal radius (r = 1.75 cm) and the length of the segment (fixed at L = 10 cm between two balloons) according to eq 1: Peff =

Q in C in − Cout × Cout 2πrL

Table 1. BCS Classification of 30 Drugs Based on Human Effective Permeability (Peff) and Dose Numbera

(1)

where Cin and Cout are the drug concentrations in the ingoing and outgoing perfusate, and Qin is the single-pass perfusion flow rate. The Peff, which is based on the rate of disappearance of the drug from the perfused jejunal segment, is a directly measured parameter of intestinal drug transport that is not influenced by other factors such as first-pass metabolism, transit, and variable lumen conditions. Two different imaging techniques showed that the human jejunal radius is between 1.61 and 1.93 cm, which validates and confirms the accuracy of the value 1.75 cm that has been used in a large number of earlier human perfusion studies.45,51,52,55−57 The total human jejunal Peff database consists of 30 drugs and are summarized together with their dose number, fraction dose absorbed (fa), and BCS class in Table 1.45,51,52,55−57 This set of drugs represents a wide physicochemical property space.25 By using a subset of these drugs and multivariate data analysis, models were derived that correlated passive intestinal permeability to physicochemical descriptors. However, these models are not applicable for predicting jejunal Peff for peptides, polysaccharides, or other compounds which do not fit into the defined property space.25 Many of the clinical studies included examination of various transport mechanisms under well-controlled luminal conditions.45,47,52,58 The human jejunal Peff values for these drugs are position- and time-dependent but are nonetheless able to predict the overall fa.45,52 Equation 1 is based on several physiological and biopharmaceutical observations and assumptions such as: (a) the binding of the drug to the tube material has been examined and corrected for; (b) the hydrodynamics in the perfused intestinal segment are best described as wellstirred;59,60 (c) any chemical and/or enzymatic degradation of the drug in the lumen (before absorption) has been investigated and accounted for; and (d) there is no

drug

human in vivo permeabilityb (·10−4 cm/s)

dose numberc

BCS Class

fa (%)

α-methyldopa amiloride amoxicillin antipyrine atenolol carbamazepine cephalexin cimetidine cyclosporine desipramine HCl enalapril maleate enalaprilat fexofenadine fluvastatin sodium furosemide hydrochlorothiazide isotretinoin inogatran ketoprofen L-dopa lisinopril losartan metoprolol naproxen piroxicam propanolol ranitidine terbutaline valacyclovir R-verapamil S-verapamil

0.10 1.6 0.30 5.60 0.20 4.30 1.56 0.26 1.61 4.50 1.57 0.20 0.07 2.40 0.05 0.04 0.99 0.03 8.70 3.40 0.33 1.15 1.34 8.50 6.65 2.91 0.27 0.30 1.66 6.80 6.80

0.1 0.4−0.8 0.9 0.20 0.02 80 2 3 350 90 75 >90 100 65 8 5−10 95 40−60 55 90 5−10 100 100 35 100 95 100 100 100 50−60 40−50 >80 100 100

a

Each Peff-value was determined in vivo in the proximal jejunum in humans with a single-pass approach at pH 6.5 (phosphate buffer) and under isotonic conditions. bHuman Peff was determined at a concentration that was based on the most common clinical dose dissolved in 250 mL. For low solubility concentration, the highest possible drug concentrations were applied. cDose number = dose/V0/ Csmin (highest dose strength/initial gastric volume (250 mL))/ minimum solubility. dHigh permeability due to carrier mediated absorption, currently not included in BCS class I. e75% at 500 mg; 45% at 3000 mg.

accumulation of drug in the gut wall or tissue, and therefore, sink conditions have been established across the intestinal epithelium. In vivo jejunal Peff values for D-glucose and antipyrine, determined at single-pass perfusion flow rates between 1.5 and 6.0 mL/min (i.e., within the physiological range), have been used to calculate the thickness of the intestinal aqueous boundary layer; values between 83 and 188 μm were obtained. Because the flow rate approximated the GI motility and extent of stirring in vivo, the rate-limiting step in the transmucosal transport of dissolved drugs is traversal of the intestinal membrane, irrespective of the extent of permeability or the transport mechanism involved.61 There is no evidence of increased intraluminal pressure within the perfused segment that might enhance paracellular absorption, since the recovery of nonabsorbable marker compounds and large/hydrophilic compounds is almost complete in the perfusate leaving the 14



Review

segment. The average volume of the perfusion solution within the perfused intestinal segment has previously been approximated to 46−75 mL at a single-pass perfusion rate of 3 mL/ min, which also indicates that there is no increased pressure within the perfused segment as the total volume of the segment is 100 mL.39 The validity of these in vivo jejunal Peff values can be further analyzed by converting them into GI absorption half-life (t1/2,abs) values and then comparing these with the corresponding t1/2,abs values calculated from plasma concentration−time profiles using traditional PK data analysis. The in vivo jejunal Peff values are thought to reflect the “true” in vivo intestinal permeability that operates following the oral administration of drugs (Figure 2a−b). The t1/2,abs values obtained from jejunal Peff values (see eq 2) for a selected subset of the drugs agreed well with “true” in vivo absorption rate data obtained in clinical PK studies where solutions or immediate-release formulations were given orally (Table 2).

τ1/2,abs =

V ln 2 Peff 2πrL

(2)

where V is the estimated average volume of the fluid inside the perfused jejunal segment (V ≈ 60 mL).39 The intestinal t1/2,abs of D-glucose at a perfusate concentration of 5−10 mM was about 6 min, which predicts that absorption will be complete within 25−30 min (∼4t1/2,abs). This agrees with data from a clinical GI intubation study where the absorption of D-glucose was completed while the drug was in the midjejunum (the small intestinal transit time to midjejunum is about 20−30 min).62 This value represents the time to maximal absorption of glucose following direct administration into the small intestine. The estimated t1/2,abs values for antipyrine, verapamil, and metoprolol are also in agreement with the actual times to achieve complete absorption from the small intestine when these drugs are given in solution or immediate-release products.46 The actual times for complete absorption (i.e., total disappearance from the intestinal lumen) of antipyrine, verapamil. and metoprolol, estimated from the t1/2,abs obtained from the plasma concentration−time profiles in separate studies, were 40−50 min, 50−60 min, and 2.5 h, respectively. These data agreed with the t1/2,abs values estimated from Peff values using eq 2 (see Table 2).46 The t1/2,abs for atenolol was approximately 7 h, which agrees with an extent of intestinal absorption of 40−50%.63,64 Atenolol is a BCS class III drug which is mainly absorbed from the small intestine with limited absorption from the colon,12,46 as shown in an open perfusion study.12 As 50% of the dose is absorbed only in the small intestine, its transit time agrees with the t1/2,abs. Terbutaline, another BCS class III drug with limited colonic uptake, has a t1/2,abs of 3.5 h, which is consistent with a somewhat higher extent of absorption (60%) than atenolol.12,65 Fexofenadine, a BCS class III drug, is slowly and incompletely absorbed from the small intestine when measured with single-pass perfusion and traditional PK studies (Table 1). Some reports have claimed that this is because of extensive intestinal efflux mediated by P-glycoprotein (P-gp).66,67 However, a number of intestinal perfusion, GI intubation, and oral and IV microdose studies in humans have not confirmed the quantitative importance of an in vivo efflux mechanism for this drug.68−71 For example, a clinical microdose study reported that the bioavailabilities of fexofenadine 100 μg and 120 mg were 40% and 28%, respectively.70,72 The 1000times difference between the two oral doses thus appeared not to markedly affect the GI absorption and bioavailability, which supports the theory that P-gp-mediated intestinal efflux is not a major factor in the intestinal absorption of fexofenadine.68,69,71,73 The in vivo jejunal Peff of fexofenadine is about 0.07 × 10−4 cm/s, and the fa is in the range of 30−40%.55,71,73 An in vitro study using the Caco-2 model indicated that P-gp was the main transport protein but was not the main reason for the slow, incomplete intestinal absorption.68,69,71,73 The Caco-2 apparent permeability coefficient (Papp) for fexofenadine (0.31 × 10−6 cm/s) remained low, approximately 1.5 × 10−6 cm/s, when P-gp was completely inhibited by the P-gp/BCRP inhibitor 120918. A Papp of about 40 × 10−6 cm/s would have been required for a predicted fa of >90% in this model.73 The low intestinal permeation of fexofenadine in vivo and in vitro was therefore interpreted to be predominantly governed by passive permeation in line with its physicochemical properties.73 It is also important to note the absence of a quantitative correlation between in vivo human jejunal Peff and in vitro Papp

Figure 2. (a−b) Determined in vivo intestinal permeability (Peff) values seem to reflect the “true” in vivo intestinal permeability in a clinical situation, as given by the calculated (see eq 2) absorption halflives (t1/2,abs) for 30 drugs (part a).45,51,52,55−57 These data agreed well with “true” in vivo absorption rate data obtained in clinical pharmacokinetic studies using solutions or immediate-release formulations (part b; see Table 1). 15



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Table 2. Human Intestinal Absorption Half-Lives (t1/2,abs) Estimated from Human in Vivo Jejunal Permeability (Peff) Values and Their Relationship to the Maximum Dose Absorbed over a Certain Time, Obtained from Equation 2 (See Text) Using the Absorption Rate Constant (ka)a compound

Peff (·10−4 cm/s)

ka (min−1)

t1/2,abs (min)

fraction absorbed (%)

time to maximum absorbed dose (min)

D-glucose atenolol terbutaline antipyrine metoprolol verapamil fexofenadine

10 0.15 0.3 5 1.5 4.0 0.07

0.110 0.002 0.003 0.055 0.016 0.044 0.001

6.3 420 210 12.6 42.0 15.8 900

100 45 65 100 100 100 30−40

20−30 300b 300b 40−50 150 50−60 300b

a

The maximum absorbed doses were obtained from pharmacokinetic studies without tubes, as described in the text.45,51,52,55−57 bPoorly permeating drugs are mainly absorbed during transit of the small intestine, over approximately 5 h.

for fexofenadine in Caco-2 monolayers (Peff/Papp = 22.6).71,73 This lack of direct correlation between in vitro and in vivo has been reported from other studies where two BCS class III drugs (terbutaline and atenolol) had a jejunal Peff/Caco-2 Papp ratio of 79 and 27, respectively.74 It is obvious that the in vitro Caco-2 Papp value needs to be properly adjusted prior to use of PBPK modeling of GI absorption. The lower Papp for passively transported compounds in the Caco-2 than in human jejunum in vivo is mainly related to lower surface area and a reduced fraction transported through the paracellular route for smaller molecules (i.e., MW approximately 250 Da and smaller).74 The contribution of paracellular absorption for fexofenadine (MW 501.6 Da) was most likely minor. The role of any carriermediated process as the major route for absorption for fexofenadine has not been presented any clear evidence in vivo in humans yet. The Peff values in Table 2 indicate that there is a human jejunal in vivo Peff cutoff point at approximately 1.5 × 10−4 cm/s (t1/2,abs of ∼42 min)45,46 that marks the difference between drugs that are rapidly absorbed (high Peff) and those that are slowly and incompletely absorbed (low Peff) from a solution. The cutoff point for the absorption rate based on in vivo jejunal perfusion data is in agreement with the simulated PK data in another study.75,76 In the PK simulation study, if the absorption had a t1/2 of 5−40 min, a high Peff was predicted (fa >90%), but if the absorption t1/2 was between 50 and 420 min, the Peff would be low as long as the absorption of the drug was not limited by the solubility/dissolution rate.75,76 However, Peff values predicted directly from absorption t1/2,abs values originating from a jejunal perfusion are expected to be somewhat higher than those calculated from the plasma concentration−time profile. In particular, BCS class III drugs will be absorbed more slowly following oral administration than indicated by jejunal perfusion data, as the proximal small intestine is more permeable than the more distal intestine and ascending colon. This is one reason why in vivo estimates of the permeability of the human distal small intestine and colon to different drugs are needed to increase the precision of in silico modeling and improve simulations of absorption from pharmaceutical dosage forms during drug development. It is important to recognize that the rate and extent of GI absorption of BCS class II drugs from solid dosage forms may also be affected by the intestinal Peff. This is because the intestinal Peff provides sink conditions that promote further dissolution in the intestinal lumen and/or adjacent to the membrane barrier.77−79 For example, the directly measured in vivo dissolution profile of carbamazepine (a BCS class II drug) based on concentrations of the drug in the solid and dissolved

states in the perfusate leaving the single-pass perfused jejunal segment has been shown to be similar to that obtained from the deconvoluted plasma concentration−time profile for the drug.62 In this study, a suspension containing carbamazepine and the nonabsorbable marker 14C-PEG 4000 was administered into the semiopen segment, using the channel in the middle of the segment. Perfusion samples were drained under gravity through the holes at each side of the perfusion tube in the segment (Figure 3). The perfusate samples leaving the segment

Figure 3. Multichannel perfusion tube Loc-I-Gut in the proximal human jejunum as used in single-pass, direct in vivo dissolution perfusion studies of carbamazepine in suspension. The distal balloon was inflated with air to create a semi-open segment. Gastric suction was applied through a separate tube placed in the antrum region of the stomach.

were collected quantitatively on ice at 5 min intervals. The collected fractions were then weighed and centrifuged at 3000 rpm for 5 min, and the supernatant and sediment were separated and immediately frozen. The two dissolution profiles of carbamazepine obtained in vitro were statistically significantly lower than the two direct in vivo dissolution approaches. The higher in vivo dissolution rate of the suspended particles was most likely a consequence of efficient sink conditions provided by the high permeability of the epithelium to carbamazepine and more pronounced intestinal motility.77−79 It is also important to consider the solubility−permeability interplay in the context of the concentration of the surfactant tablet excipient in vivo. The free fraction of drug in the lumen will be reduced as the concentration of the surfactant increases above the critical micelle concentration. Reducing the fraction 16



Review

Table 3. Steady-State in Vivo Intestinal Permeability (Peff) Calculated Using the Parallel-Tube Modela for One Amino Acid (See Figure 4) and 11 Different Drugs46,89−95 drug substance

segment length (cm)

perfusion rate (mL/min)

Peff, jejunum (·10−4 cm/s)

Peff, ileum (·10−4 cm/s)

fa (%)

BCS Class

Peff, jejunum/Peff, ileum

hydrocortisone triamcinolone acetonide paracetamol salicylic acid griseofulvine cimetidine furosemide atenolol talinolol ranitidine hydrochlorothiazide

15 15 30 80 20 80 80 80 30 30 80

15 15 10 5 10 5 5 5 10 10 5

8.8 4.9 4.8 2.7 7.0 0.75 0.5 0.4 0.3 0.3 0.2

5.6 10 7.1 2.5 8.0 0.25 0.2 0.25 0.4 0.1 0.15

90 95 90 100 90 64 55 55 40 50 50

II II I I II III IV III IV III IV

1.6 0.5 0.7 1.1 0.9 3.0 2.5 1.6 0.8 3.0 1.3

a

The investigated intestinal segment varied in length between 15 and 80 cm, and the perfusion rates varied between 15 and 5 mL/min; fa = fraction of dose absorbed.

intestine Peff values and are therefore difficult to directly adapt into a PBPK GI absorption model without rational scaling.87 However, the Caco-2 model does reliably predict colonic permeability to drugs, which is in accordance with its origin as a colonic carcinoma.12 This suggests that in vitro permeability data from the Caco-2 model can often predict whether a drug can be formulated as a modified-release dosage form, with most of the absorption occurring from the colon.12,45,87 However, practical limitations in the in vitro assessment for some low solubility may lead to misclassification.84 Regional Differences in Absorption of Drugs and Nutrients from the Human Small Intestine Determined by Open, in Vivo, Single-Pass Perfusion Systems. An average human Peff value representative for the total intestine was used in the development of an in silico model of the GI absorption of nilotinib.81 However, the permeability of each specific part of the intestine has to be taken into account in a more physiological manner in order to be able to further improve use of these in silico tools in the early design and development of advanced modified-release products. In this section, some human Peff values from different regions of the small intestine will be presented to illustrate our limited accuracy of the permeation of drug molecules to cross the small intestinal and colonic epithelium in vivo in humans. Some human permeability data are derived from studies using open single-pass perfusion systems under various conditions;46,89−95 there are also data from numerous animal studies.5,96 The investigated intestinal segment in these clinical studies varied in length (15, 20, 30, and 80 cm), and the perfusion rates were 15, 10, and 5 mL/min. The steady-state intestinal Peff was calculated using the parallel-tube model for one amino acid and 11 different drugs.46,89−95 This hydrodynamic model was applied as the segment was perfused from the entrance at one end of the intestinal segment to the exit at the other end at a rather high perfusion rate (eq 3):60

of free drug will significantly decrease the amount of drug available for intestinal membrane permeation, as observed in several studies.80 The GI absorption of lipophilic basic drugs is also interesting from a biopharmaceutical viewpoint. Nilotinib (MW: 529.5; free base; pKa: 2.1 and 5.4; polar surface area, PSA: 97.6; partition coefficient, logP: 5.2; melting point: 230− 242 °C) is a targeted anticancer drug that is administered orally as the hydrochloride salt and exhibits pH-dependent aqueous solubility. In vitro confluent Caco-2 monolayers are only moderately permeable to nilotinib.81,82 Based on this and its poor aqueous solubility (dose number ∼160), nilotinib is classified as a BCS class IV compound (low solubility and poor permeation).81,82 Interestingly, according to BDDCS nilotinib is a BDDCS class II drug (low solubility, good permeation,), and it is extensively metabolized.82 However, in a recent in silico prediction of the GI absorption and bioavailability of nilotinib following oral administration, the human Peff used in the GastroPlus model was 1.5 × 10−4 cm/s, which is similar to that for metoprolol and to the cutoff value between low and high jejunal permeability.12,45,52,83 Metoprolol is a BCS class I drug which permeates well through the intestine, including the colon.12 Thus, there was better agreement of permeability classification between BDDCS and the human intestinal permeability obtained in the in silico modeling of GI absorption of nilotinib.81 Although the in vitro permeability in Caco-2 cells to some BCS class II drugs appears to be low, it may have explained practical limitations as these drugs have very low solubility and this may have contributed to the low permeability classification.84 It is clear that results from the in vitro Caco-2 cell system are not always directly correlated to human small intestinal permeability predictions even for BCS class II drugs and may require scaling factors. The in vitro/in vivo correlation between different in vitro or in situ models and human in vivo Peff values is a crucial parameter in determining predictions of GI drug absorption.25,53,54,85−87 The passive transcellular movement of drugs is determined by their lipophilicity and the effects of chain ordering, which may differ between in vivo biological membranes and various in vitro models. It is not easy to predict the absorption of drugs by carrier-mediated mechanism(s) and/or by the paracellular route (which overall is a minor absorption route for most drugs) across the small intestine using the Caco-2 monolayer model.85,88 The Papp values for these carrier-mediated transported drugs are significantly lower than in vivo proximal small

Peff = −

Q in ln(Cout /C in) 2πrL

(3)

where Cin/Cout is the ratio of the entering and leaving concentrations of the investigated drug, adjusted for water transport, and A is the mass transfer surface area within the intestinal segment, which is assumed to be a cylinder with a length of 15, 20, 30, or 80 cm and a radius (r) of 1.75 cm (jejunum) or 1.5 cm (ileum).46,89−95 17



Review

Table 3 shows the investigated drugs, their BCS class, and the regional Peff values. The mean (±SD) ratio between in vivo jejunal and ileal Peff for these 11 drugs (representing all BCS classes) was 1.5 ± 0.9. The mean ratio for the six poorly permeating drugs (BCS classes III and IV) in the table was 2.0 ± 0.9. The difference between these values could be explained by differences in mucosal surface area for a given length of intestine. The absorption characteristics of the rat small and large intestine have been shown in several studies to be similar to and to correlate well with those of human intestine5,38,53 A study in 1950 of rat small intestine showed that the ratio of mucosal surface area for a given length of intestine between rat jejunum and ileum was 2.97 The agreement between these estimates confirms that the available mucosal surface area is an important factor, supports the suggestion that the surface area is twice as extensive in the jejunum as in the ileum, and suggests that poorly permeating drugs use a larger fraction of the cryptvillus axis than the cylinder surface area used for the highly permeating drugs. In a study where a number of drugs were investigated in the Ussing chamber model using rat intestinal tissue, the jejunal/ileal Papp ratios for the freely and poorly permeating drugs were 0.7 ± 0.17 and 1.4 ± 0.39, respectively.5 The local transport kinetics of ropivacaine and its metabolite 2′,6′-pipecoloxylidide (PPX) were also assessed from their concentration−time profiles in the mucosal and serosal compartments of a modified Ussing chamber using small and large intestinal specimens from 11 human patients.98 The permeability (Papp) of the specimens in the absorptive direction increased regionally in the order jejunum < ileum < colon for the freely permeating ropivacaine and the somewhat more hydrophilic PPX.98 This pattern has been reported for other regional permeability studies investigated in the Ussing chamber using intestinal specimens from both humans and rats.5,52,54,99 The reasons for these differences in permeability and how they can be accounted for need further investigation. The Peff values for L-methionine and 11 drugs in human jejunum and ileum are shown in Figures 4 and 5, respectively.46,89−95 The absorption of L-methionine was investigated in an open, single-pass perfusion with four entering concentrations in human jejunum and ileum (Figure 4). L-

Figure 5. Summary of the in vivo effective permeability (Peff) of human jejunum and ileum to 11 drugs.46,89−95 The perfused small intestinal segment was 20, 30, or 80 cm long, and the single-pass perfusion rates were 5, 10, or 15 mL/min. The Peff was calculated using eq 3.

Methionine is a small (MW 149.2), nonpolar, essential amino acid that is in zwitterionic form at neutral pH. The permeability of both jejunum and ileum to the compound was high and concentration-dependent. The transport capacity (Vmax) was higher in the jejunum than in the ileum, in accordance with data shown in Figure 4.94 The rapid permeation across the intestine for this amino acid agreed with data for other nutrients such as L-phenylalanine, L-leucine, and D-glucose that were determined using the single-pass perfusion, doubleballoon technique Loc-I-Gut.45,52 The human jejunal Peff for the structurally similar sulforaphane was 18.7 × 10−4 cm/s.100 The permeability of both human jejunum and ileum to hydrocortisone was high in these studies (Table 3 and Figure 5). The usefulness of these biopharmaceutical parameters can be demonstrated in the pharmaceutical development of the novel oral, once-daily, modified-release dosage form of hydrocortisone that is used to treat adrenal insufficiency.101 This modified-release tablet resulted in a more circadian-based serum cortisol profile that achieved the following effects: reduced body weight, reduced blood pressure, and improved glucose metabolism during treatment. In particular, glucose metabolism improved in patients with concomitant diabetes mellitus.102 The regional Peff values in Figures 4 and 5 indicate that human intestinal permeability determinations made with open, single-pass, perfusion methods under different hydrodynamic conditions and using calculations based on the parallel-tube model produce data that agree with the more well-controlled human jejunal data obtained using the Loc-I-Gut system, despite the lower recovery of the perfusate leaving the segment.46 The human jejunal Peff values from the Loc-I-Gut method for cimetidine, furosemide, atenolol, ranitidine, and hydrochlorothiazide were 0.26, 0.05, 0.20, 0.27, and 0.04 × 10−4 cm/s, respectively.45,46,52,89−95 The corresponding data in the open perfusion system from jejunum were 0.75, 0.5, 0.4, 0.3, and 0.2 × 10−4 cm/s, respectively. The general trend with higher Peff in the open system for drugs from all BCS classes may be explained by differences in absorption conditions such as pH, fluid corrections, recovery of the fluids leaving the segment, and fluid dynamics. The 10-fold higher jejunal Peff in the open system for furosemide might be related to differences in pH in the test segment. Furosemide (weak acid with pKa’s of

Figure 4. In vivo effective permeability (Peff) of human jejunum and ileum to L-methionine was investigated at different concentrations of drug entering the single-pass perfused intestinal segment.46,89−95 The perfused small intestinal segment was 15 cm long, and the single-pass perfusion rate was 15 mL/min. Peff was calculated using eq 3. 18



Review

absorption.103,105,114−120 It has been reported that 42 BCS class I drugs were well-absorbed in the colon [Frel‑colon (bioavailability) > 70%] in a comparison of the plasma exposure of the drug following oral and colonic administration.12 The low Peff drugs (BCS class III/IV) were less well absorbed in the colon (Frel‑colon < 50%). Interestingly, there was a clear correlation between in vitro Caco-2 permeability and Frel‑colon, which is in agreement with the observation that Caco-2 is a better transport model for prediction of absorption in the large intestinal than the small intestine. Data reported by Tannergren et al. in 2009 support the suggestion that atenolol and metoprolol could function as Peff markers for low and high colonic absorption, respectively.12 No obvious effects of P-gp on colonic absorption were established for the investigated drugs.12 However, even if this study showed progress in the understanding of colonic drug absorption, it was clearly identified that further improvements of in silico predictions of absorption from modified-release dosage forms need access to better in vivo data for regional intestinal Peff.12 Mechanistic physiologically based modeling of GI absorption requires that input parameters such as regional intestinal permeability need to be accurate in order for the in silico model to be accepted as a rational tool in future dosage form design and development.

3.34 and 10.46) has log D values that are increasing by reducing pH (log D7.4 −0.9; log D6.5 −0.4 and log D5.5 0.4), which predicts that it will have a pH-dependent passive intestinal permeation.25 These data confirm that the most permeable segments of the intestine for both passive diffusion and carriermediated transport are located in the jejunum, unless other effects such as the interplay between pKa and the luminal pH favor absorption from the ileum (Figures 4 and 5). One such example of the pH-dependent permeation is sotalol, which had a higher Peff in ileum compared to jejunum in rats.83 In Vivo Colonic Drug Absorption in Humans and Rats. The colonic absorption of drugs can differ significantly from absorption in the small intestine as a consequence of several physiological, physicochemical, and biopharmaceutical factors.103−109 Modified-release formulations are designed to control the absorption rate, the plasma concentration−time profile, and consequently the pharmacodynamics of the drug by controlling its rate of release from the formulation. The applicability of BCS for modified-release products and colonic absorption has been discussed previously.12,103,105,110 The permeability through passive transport is thought to be lower in colonic than in other intestinal tissue because of the smaller surface area and tighter junctions in the epithelial cell layer.5,99 There have not been any direct measurements of in vivo colonic Peff for drugs in humans to date. A few perfusion studies have been perfomed in colon, but often then is the total colon perfused. Usually, it takes 1−3 days to reach human cecum, and then the perfusion solution is collected via a rectal catheter inserted 5−10 cm above the anal verge. 111,112 Basic physiological and pathophysiological processes have been the focus in such perfusion experiments of colon.113 However, the rectal in vivo Peff has been determined for phenoxymethylpenicillin, antipyrine, and sodium caprate in human volunteers using regional singe-pass rectal perfusion.49,50 These in vivo rectal Peff values correlated well with log D values at pH 7.4, as shown in Figure 6. In addition, the expression of efflux and uptake transporters such as P-gp and the human di/tripeptide transporter (hPepT1) appears to increase and decrease in the colon, which may limit the permeability, dissolution rate, and

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CONCLUSIONS There is a need for more exploratory in vivo studies to clarify regional drug absorption along the intestine, especially in the colon. Development of experimental and theoretical methods of assessing the permeability of distal parts of the GI tract in humans is particularly encouraged. It is now recognized that important differences between in vivo models, species, and in vitro transport models in the Ussing chamber and cell monolayers (such as the Caco-2 model) do not serve the purpose of improving the accuracy of in silico absorption models as they need to introduce validated scaling factors. Developing new in vivo methods would stimulate the development of more relevant and complex in vitro absorption models and form the basis of an accurate, physiologically based PK model of GI drug absorption. The importance of accurately determining input parameters in such a model is crucial for increasing the acceptance of these models and simulation of GI drug absorption.

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AUTHOR INFORMATION

Corresponding Author

*Telephone: +46 18 471 43 17. Fax: +46 18 471 42 23. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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REFERENCES

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Figure 6. Relationship between the lipophilicity of three compounds and the in vivo effective permeability (Peff) of the rectum to these compounds in humans as obtained from a single-pass rectal perfusion.50 There was no absorption of D-glucose from the human rectum, which is in accordance with its hydrophilicity and the absence of functional glucose transporters.49 19



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Human in Vivo Regional Intestinal Permeability: Importance for

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