Regional intestinal drug permeation: Biopharmaceutics and drug development

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Contents lists available at ScienceDirect

European Journal of Pharmaceutical Sciences journal homepage: www.elsevier.com/locate/ejps

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Review

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Regional intestinal drug permeation: Biopharmaceutics and drug development

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Hans Lennernäs ⇑

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Uppsala University, Sweden

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a r t i c l e

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i n f o

Article history: Received 4 June 2013 Received in revised form 12 August 2013 Accepted 13 August 2013 Available online xxxx

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Keywords: Biopharmaceutics Biopharmaceutical classification system PBPK IVIVC Dissolution Drug absorption

a b s t r a c t Over the last 25 years, profound changes have been seen in both the development and regulation of pharmaceutical dosage forms, due primarily to the extensive use of the biopharmaceutical classification system (BCS) in both academia and industry. The BCS and the FDA scale-up and post-approval change guidelines were both developed during the 1990s and both are currently widely used to claim biowaivers. The development of the BCS and its wide acceptance were important steps in pharmaceutical science that contributed to the more rational development of oral dosage forms. The effective permeation (Peff) of drugs through the intestine often depends on the combined outcomes of passive diffusion and multiple parallel transport processes. Site-specific jejunal Peff cannot reflect the permeability of the whole intestinal tract, since this varies along the length of the intestine, but is a useful approximation of the fraction of the oral dose that is absorbed. It appears that drugs with a jejunal Peff > 1.5  104 cm/s will be completely absorbed no matter which transport mechanisms are utilized. In this paper, historical clinical data originating from earlier open, single-pass perfusion studies have been used to calculate the Peff of different substances from sites in the jejunum and ileum. More exploratory in vivo studies are required in order to obtain reliable data on regional intestinal drug absorption. The development of experimental and theoretical methods of assessing drug absorption from both small intestine and various sites in the colon is encouraged. Some of the existing human in vivo data are discussed in relation to commonly used cell culture models. It is crucial to accurately determine the input parameters, such as the regional intestinal Peff, as these will form the basis for the expected increase in modeling and simulation of all the processes involved in GI drug absorption, thus facilitating successful pharmaceutical development in the future. It is suggested that it would be feasible to use open, singlepass perfusion studies for the in vivo estimation of regional intestinal Peff, but that care should be taken in the study design to optimize the absorption conditions. Ó 2013 Published by Elsevier B.V.

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Contents 1. 2. 3. 4. 5. 6. 7. 8.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Definition of intestinal absorption and bioavailability. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Permeability of human jejunum to drugs and nutrients in vivo, estimated as Peff determined by double-balloon perfusion. . . . . . . . . . . . . . . . . Permeability of different regions of the human small intestine to drugs and nutrients, estimated as Peff determined by open perfusion systems In vivo colonic drug absorption in humans. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . In vitro and in vivo correlation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Is animal a good model for intestinal permeability of drugs in humans? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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⇑ Tel.: +46 18 471 43 17; fax: +46 18 471 42 23.

1. Introduction

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The biopharmaceutical classification system (BCS) (Amidon et al., 1995) and the FDA guidelines for scale-up and post-approval

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E-mail address: [email protected] 0928-0987/$ - see front matter Ó 2013 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.ejps.2013.08.025

Please cite this article in press as: Lennernäs, H. Regional intestinal drug permeation: Biopharmaceutics and drug development. Eur. J. Pharm. Sci. (2013), http://dx.doi.org/10.1016/j.ejps.2013.08.025

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changes (SUPAC) were developed during the 1990s, and both have facilitated the development of pharmaceutical products over the last two decades. In silico models and simulations of drug absorption, distribution and excretion, which are becoming increasingly important in the development of oral pharmaceutical products, aim to reduce time, effort and costs by decreasing the number of in vivo bioequivalence studies needed. One recent European research effort working in this area, extensively covered in this special issue of the European Journal of Pharmaceutical Sciences (EJPS), is the IMI OrBiTo (Oral Biopharmaceutics Tools) project. The main objective of OrBiTo is to develop novel experimental and theoretical simulation tools (in silico) to be used in pharmaceutical research and development, and the regulation of oral pharmaceutical products (http://www.imi.europa.eu/content/orbito). Membrane transport proteins are known to influence the absorption of some drugs. The Biopharmaceutics Drug Disposition Classification System (BDDCS) was developed to predict the influence of these proteins on biopharmaceutic and pharmacokinetic (PK) processes and parameters (Wu and Benet, 2005). A recently published compilation of the BDDCS classifications for 927 drugs (includes 30 active metabolites). Of the 897 parent drugs examined, 80% are administered orally (Benet et al., 2011). Discussions are also under way on the advisability of substituting the degree of metabolism of the drug in drug development simulations as an alternative surrogate for the extent of intestinal permeation and the fraction of the dose absorbed (fa) (Chen et al., 2011). The BCS and the BDDCS classify approved drugs and new drug candidates into four categories using the same solubility criteria, but differ in their permeability criteria and have different purposes (Benet, xxxx). The BCS system is currently widely applied in regulatory affairs and has a significant direct industrial impact (Ungell et al., 1998; Lennernas and Abrahamsson, 2005; Amidon et al., 2011; Dahan et al., 2012). Together, the BCS, the BDDCS, modeling, and simulation are central to the evolution of biopharmaceutical and PK concepts and have a large impact on drug discovery, drug development and regulatory strategies in the pharmaceutical industry (Benet, 2013; Smith, 2013). The BCS has recently been extended to form the Developability Classification System (DCS) (Butler and Dressman, xxxx)). This revised system has been designed to have a greater focus on drug developability and specifically to predict what pharmaceutical factors are critical to in vivo performance and critical quality attributes. For instance, DCS introduced the concept of solubility limited absorbable dose (SLAD), which might be able to more easily titrate the dose above which gastrointestinal (GI) absorption is likely to be limited by intestinal solubility. More exploratory in vivo studies are needed to clarify regional drug absorption along the intestine, especially in the colon. The development of experimental and theoretical methods of directly 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 fully serve the purpose of improving the accuracy of in silico absorption models. Developing new in vivo methods would stimulate the development of more relevant and complex in vitro absorption models, and would form the basis of an accurate, physiologically based PK (PBPK) model of GI drug absorption (Darwich et al., xxxx; Poulin et al., xxxx; Agoram et al., 2001; Parrott et al., 2009). The importance of accurately determining the input parameters in such a model cannot be overstated; this step is crucial for increasing the acceptance of these models in simulating GI drug absorption. The experimental and in silico models applied in the design and development of oral pharmaceutical products need to improve to be able to better predict the key biopharmaceutical and PK

processes. The main biopharmaceutical parameters for an active pharmaceutical ingredient (API) include its physical, chemical, and biological properties, the design and composition of the pharmaceutical formulation, and the extent and manner of GI absorption. The permeation of drugs through the intestinal wall varies along the small and large intestine and is extensively influenced by any transport mechanisms involved (Ungell et al., 1998; Tannergren et al., 2009; Sjoberg et al., 2013) (Sugano et al., 2010). It Q4 is important to distinguish between these transport routes and to identify the main membrane transport mechanism(s) for each drug. It is recognized that no in vitro model can accurately predict the permeability of the small intestine to compounds, which have slow passive diffusion and/or carrier-mediated transport as the main transport mechanism (Sun et al., 2002; Lennernas, 2007a, 2007b; Dahan et al., 2009b; Larregieu and Benet, 2013). The primary objective of this review is to present and critically discuss the differences in permeability between various regions of the human intestine, as estimated by the effective permeation (Peff) of drugs through the intestinal wall, and to relate these human in vivo data to in vitro cell culture data.

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2. Definition of intestinal absorption and bioavailability

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Most orally administered drug products have pharmacological and adverse effects that to various degrees are related to the rate and/or extent of the absorption and bioavailability (F) of the API. In a regulatory context, F is defined as the rate at and extent to which an API is released from the pharmaceutical dosage form to become available in the general circulation (often the plasma compartment). F is mainly dependent on three general but rather complex serial processes: the fa, the extent of first-pass extraction of the drug by enzymes in the gut wall (EG), and the extent of firstpass extraction of the drug in the liver (EH) (Eq. (1)) (Amidon et al., 1995; Wu et al., 1995).

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F ¼ fa  ð1  EG Þ  ð1  EH Þ

ð1Þ

135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153

156 157 158 159 160 161 162 163 164 165

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Accordingly, the rate (mass/time) and extent (fa = mass/dose) of drug absorption following oral administration in vivo are influenced by: the ratio of dissolved drug (solubility) to the administered dose; the rate and extent of chemical degradation or metabolism in the lumen, GI luminal complex binding, and GI transit; and the Peff across the intestinal mucosa. The Peff and the dissolved and free drug luminal GI concentrations are the key variables controlling the fa (Amidon et al., 1995, 2011; Sun et al., 2002; Tannergren et al., 2003b). The successful development of a theoretical PBPK model for GI drug absorption requires in vivo Peff data for a set of drugs representing the different absorption properties of different intestinal segments.

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3. Permeability of human jejunum to drugs and nutrients in vivo, estimated as Peff determined by double-balloon perfusion

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The single-pass, double-balloon perfusion system is a directly measured parameter of intestinal drug transport that is not influenced by other factors such as the extent or rate of metabolism, methods of transit or lumen conditions. The estimation of Peff is based on the rate of disappearance of the drug from the perfused jejunal segment, where the difference between the concentrations of substance entering and leaving the tested segment is determined (or the rate of its appearance in the segment if direct intestinal secretion is examined). The absorption conditions, such as pH, osmolality, fluid correction and recovery of the perfusion fluids, which differ significantly among the clinical methods applied, need to be considered in the design and evaluation of these experiments.

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The human jejunal Peff values estimated using these methods are position- and time-dependent, but have been shown to predict the overall rate and extent of intestinal drug absorption (Lennernas, 2007b, 2007c). Four slightly different single-pass perfusion methods have been used to directly determine the intestinal Peff in humans: (i) a triplelumen tube with a mixing segment, (ii) a multilumen tube with a Ò proximal occluding balloon, (iii) a multilumen tube (Loc-I-Gut or Loc-I-Col) with two balloons occluding a 10 cm intestinal segment, and (iv) isolation of two adjacent 20 cm jejunal segments using a multilumen perfusion catheter ((Modigliani et al., 1973a, 1973b; Rambaud et al., 1973; Lennernas et al., 1992, 1994; Lennernas, 1998; Sandstrom et al., 1998) (von Richter et al., 2001; Tannergren et al., 2003a; Igel et al., 2007). Human in vivo Peff estimates for 28 drugs and 11 other compounds have been determined using the third of these techniques Ò (the double-balloon Loc-I-Gut method) in the proximal jejunum without the use of any systemically administered anesthesia (Fagerholm et al., 1996, 1999; Lennernas et al., 1997b; Lennernas, 2007b, 2007c). More than 80% of the available human jejunal Peff values obtained using the double-balloon approach were determined in one laboratory; these data have been summarized elsewhere (Sandstrom et al., 1999; Lennernas et al., 2002b; Tannergren et al., 2003a, 2004; Lennernas, 2007b, 2007c). Peff was estimated using the following equation:

Peff

C in  C out Q in ¼  C out 2prL

ð2Þ

where Cin and Cout are the drug concentrations in the ingoing and outgoing perfusate and Qin is the single-pass perfusion flow rate. The cylindrical area representing the jejunal segment (2prL) was calculated using the intestinal radius (r) and the length of the segment (L; fixed at 10 cm between the two balloons). An intestinal radius of 1.75 cm was used. This value has been validated using two different imaging techniques which demonstrated that the human jejunal radius is between 1.61 and 1.93 cm (Sandstrom et al., 1999; Lennernas et al., 2002b; Tannergren et al., 2003a, 2004; Lennernas, 2007b, 2007c). Eq. (2) is based on several physiological and biopharmaceutical observations and assumptions, including: (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 modeled as well-stirred; (c) any chemical and/or enzymatic degradation of the drug in the lumen (before absorption) has been investigated and accounted for; (d) there is no accumulation of drug in the gut wall or tissue and therefore sink conditions have been established across the intestinal epithelium; and (e) a smooth cylinder surface area is available for absorption. Since, in vivo, the unstirred water layer in the intestine is thin as a result of the rigorous stirring induced by motility, the intestinal membrane is the ratelimiting step in the transmucosal transport of any dissolved drug irrespective of BCS permeability class or transport mechanism (Lennernas et al., 1997a). There is no indication that increased intraluminal pressure within the perfused segment might enhance paracellular absorption, as evidenced by the almost complete recovery of non-absorbable marker compounds and large/hydrophilic compounds in the perfusion solution leaving the segment (Sandstrom et al., 1999; Lennernas et al., 2002b; Tannergren et al., 2003a, 2004; Lennernas, 2007b, 2007c). The average volume of the perfusion solution within the perfused intestinal segment has been approximated as 46–75 mL at a single-pass perfusion rate of 2-3 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 (Knutson et al., 2009). The same four direct methods listed above for estimation of Peff have also been used to investigate various transport mechanisms

in the human intestine. Several of the clinical studies investigating transport mechanisms have used well controlled luminal conditions (Sinko et al., 1991; Lennernas et al., 1992; Lennernas, 2007b, 2007c).

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4. Permeability of different regions of the human small intestine to drugs and nutrients, estimated as Peff determined by open perfusion systems

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In this section, human Peff values from different regions of the small intestine will be presented and briefly discussed. Some of the presented human absorption data for drugs and other substances were derived from studies using open, single-pass perfusion systems under a range of GI conditions (Schedl and Clifton, 1963; Schedl, 1965; Schedl et al., 1968; Gramatte, 1994; Gramatte et al., 1994, 1996; Gramatte and Richter, 1994; Lennernas, 1998). The assumptions outlined in the previous section for the optimal performance and evaluation of clinical perfusion experiments is also valid for open and semi-open systems (except for the hydrodynamics; see below). The set-ups for these studies involved single-pass perfusion from an entrance at one end of the intestinal segment to be tested to the exit at the other end, with a relatively high perfusion rate. These open systems were constructed to allow the perfusion fluid to pass first through a mixing segment and then through the test segment; samples were obtained at the start and end of the test segment, representing the concentrations entering (Cin) and leaving (Cout) the perfused intestinal site (see Eq. (3)). The semi-open perfusion system has no mixing segment, just a test segment for single-pass perfusion. No differences between these approaches in electrolyte transport or water movement have been found during direct comparison (Mekjian et al., 1971; Modigliani and Bernier, 1971; Modigliani et al., 1973a, 1973b; Modigliani et al., 1978). The test segment varied in length in these studies from 15 cm to 20 cm, 30 cm, and 80 cm, and perfusion rates of 15 ml/min, 10 ml/min and 5 ml/min have been used. The small intestinal Peff values for one amino acid and 11 drugs have been calculated using the parallel-tube model (Eq. (3)) (Schedl and Clifton, 1963; Schedl, 1965; Schedl et al., 1968; Gramatte, 1994; Gramatte et al., 1994, 1996; Gramatte and Richter, 1994; Lennernas, 1998). In this review, the most appropriate model using hydrodynamics for calculating Peff based on data from open and semi-open perfusion systems in humans is considered to be the parallel tube model:

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Peff ¼ 

Q in ln



C out C in

2prL

 ð3Þ

where Cin and Cout are the entering and leaving concentrations (corrected for fluid transport), respectively; Qin is the single-pass perfusion flow rate; and 2prL is the mass transfer surface area within the intestinal segment, which is assumed to be a cylinder with a length of 15 cm, 20 cm, 30 cm, or 80 cm and a radius of 1.75 cm or 1.5 cm in jejunum and ileum, respectively (Schedl and Clifton, 1963; Schedl, 1965; Schedl et al., 1968; Gramatte, 1994; Gramatte et al., 1994, 1996; Gramatte and Richter, 1994; Lennernas, 1998). L-methionine is a small (MW 149.2), non-polar essential amino acid that is in its zwitterionic form at neutral pH. Its absorption was investigated using an open, single-pass perfusion at four entering concentrations. Fig. 1 shows that the Peff values for Lmethionine, although consistently higher in the jejunum than in the ileum, increased with decreasing concentrations of the amino acid in both jejunum and ileum (Schedl and Clifton, 1963; Schedl, 1965; Schedl et al., 1968; Gramatte, 1994; Gramatte et al., 1994, 1996; Gramatte and Richter, 1994; Lennernas, 1998). In another study, the transport capacity (Vmax) of L-methionine was also shown to be higher in the jejunum than in the ileum, in accordance

Please cite this article in press as: Lennernäs, H. Regional intestinal drug permeation: Biopharmaceutics and drug development. Eur. J. Pharm. Sci. (2013), http://dx.doi.org/10.1016/j.ejps.2013.08.025

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Jejunum Ileum

Human Peff (10-4 cm/s)

20

15

10

5

0 1

6 mM

2

12 mM

3

25 mM

4

50 mM

5

100 mM

Perfusate Conc. of L-Methionine Fig. 1. The in vivo permeabilitity values of human jejunum and ileum to L-methionine were investigated using different concentrations of substance entering the single-pass perfused intestinal segments (Schedl and Clifton, 1963; Schedl, 1965; Schedl et al., 1968; Gramatte, 1994; Gramatte et al., 1994, 1996; Gramatte and Richter, 1994; Lennernas, 1998). The perfused small intestinal segment was 15 cm long and the single-pass perfusion rate was 15 ml/min. The effective permeation (Peff) of L-methionine was calculated using Eq. (3) (see text) and assuming a parallel tube model. Conc. = concentration of L-methionine. 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347

with the data shown in Fig. 1 (Schedl et al., 1968). The small intestinal Peff of this amino acid was in the range 2.1–20  104 cm/s, which is in agreement with data for other nutrients such as L-phenylalanine, L-leucine and D-glucose (4.1  104, 6.2  104, 10  104 cm/s, respectively), as determined using the double-balloon Ò technique (Loc-I-Gut ) (Lennernas, 1998, 2007b, 2007c; Lennernas et al., 2002b). The Peff for the structurally similar organosulfur compound sulforaphane (MW 177.3) through the human jejunum has been estimated at approximately 19  104 cm/s (Petri et al., 2003). These amino acid data are representative of the carriermediated absorption process, and were similar for double-balloon and open single-pass perfusion systems in humans. This observation supports the use of an open perfusion system to determine human regional Peff values that will be used in the development of PBPK models and simulations of the GI drug absorption process (http://orbitoproject.eu). The human jejunum and ileum Peff values of 11 drugs are shown in Table 1. The fa and the BCS class are also provided for each drug. The class II drug hydrocortisone permeated well (Peff approximately 1.6  104 cm/s) through both jejunum and ileum (Table 1). This intestinal Peff provides key biopharmaceutical information and was recently very useful in the development of a novel oral, once-daily, modified-release dosage form of

hydrocortisone that is now used to treat adrenal insufficiency (Johannsson et al., 2009). This dual-release tablet is administered in the morning and provides a circadian-based serum cortisol profile during the daytime. This is possible because the drug permeates both the small and large intestines sufficiently well, so that the rate-limiting step in the absorption process is the slow release from the controlled-release part of the dosage form. The physiological daytime cortisol plasma concentration-time profile resulted in a positive benefit:risk ratio with outcomes such as reduced body weight, reduced blood pressure, and improved glucose metabolism. In particular, glucose metabolism improved in patients with concomitant diabetes mellitus (Johannsson et al., xxxx). This illustrates how knowledge gained from biopharmaceutics can be applied to benefit development efficiency and product performance in patients. Ò The Loc-I-Gut Peff values for class III/IV drugs cimetidine, furosemide, atenolol, ranitidine and hydrochlorothiazide in the human jejunum were 0.26, 0.05, 0.20, 0.27 and 0.04  104 cm/s, respectively (Schedl and Clifton, 1963; Schedl, 1965; Schedl et al., 1968; Gramatte, 1994; Gramatte et al., 1994, 1996; Gramatte and Richter, 1994; Lennernas, 1998, 2007b, 2007c). The corresponding data for the jejunum in a study using the open perfusion system were 0.75, 0.5, 0.4, 0.3 and 0.2  104 cm/s, respectively (Fig. 3). It thus appears that intestinal Peff data from open perfusion systems are systematically higher than those from the double-balloon approach for these drugs (Fig. 2). The differences between the two perfusion methods could be explained by differences in absorption conditions (such as pH), fluid corrections, recovery of the fluids leaving the segment, or fluid dynamics. The 10-fold higher jejunal Peff of furosemide with the open system could, for example, have been caused by differences in the pH of the test segment. The distribution coefficient (log D) of furosemide (which is a weak acid with acid dissociation constant [pKa] values of 3.34 and 10.46) increases with reducing pH (log D7.4 0.9; log D6.5 0.4 and log D5.5 0.4), which indicates that its permeation of the intestine will be pHdependent, via passive transport (Winiwarter et al., 1998). In addition, both hydrochlorothiazide and furosemide are diuretics, which could directly affect ion transport in the intestinal epithelium, and could also contribute to the high variability observed. Both these drugs are classified as having highly variable GI absorption, which means that absorption is very sensitive to the GI luminal conditions (Grahnen et al., 1984). The data from the two perfusion methods for the three other drugs (cimetidine, ranitidine and atenolol) were similar (Fig. 2). These results suggest that, in order to obtain accurate in vivo data from different intestinal sites that can be used in the development of in vitro and in silico methods, the absorption conditions need to be carefully considered. In addition, it is possible to use these intestinal perfusion methods to determine and investigate the transport mechanisms of substances that are ab-

Table 1 The steady-state in vivo intestinal effective permeation (Peff) values of 11 drugs were calculated using the parallel-tube model (Schedl and Clifton, 1963; Schedl, 1965; Schedl et al., 1968; Gramatte, 1994; Gramatte et al., 1994, 1996; Gramatte and Richter, 1994; Lennernas, 1998). The fraction of the dose absorbed (fa) and the Biopharmaceutic Classification System (BCS) class are provided. The investigated intestinal segment was 15 to 80 cm in length, and the perfusion rates were 15 ml/min or 5 ml/min. Drug

Test segment length (cm)

Perfusion rate (ml/min)

Peff, jejunum (104 cm/s)

Peff, ileum (104 cm/s)

fa (%)

BCS class

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 1.3 0.75 0.5 0.4 0.3 0.3 0.2

5.6 10 7.1 2.5 1.5 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

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cimetidine ranitidine atenolol furosemide hydrochlorothiazide

0.8

Human Peff (10-4 cm/s)

0.7 0.6 0.5 0.4 0.3 0.2 0.1

5

sorbed by passive diffusion or carrier-mediated transport. However, it is crucial to consider the absorption conditions and to monitor the experiments in vivo carefully, particularly the interplay between pKa and the pH of the perfusion solution. This has been clearly shown that the intestinal permeability is pH-dependent which is in accordance with the pH partioning hypothesis (Dahan et al., xxxx; Fairstein et al., xxxx) In these studies pH-differences along the GI-tract explained site-dependent permeability. The overall GI absorption is also affected by pH in a more complex way as it affects solubility and dissolution of the API (Tsume et al., xxxx; Charman et al., 1997). In addition, it has been shown that the absorption of a non-proteolyte can be affected indirectly as the pH influence the ionization and mixed micelles composition (Pedersen et al., 2000).

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5. In vivo colonic drug absorption in humans

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Drug absorption from the colon can differ significantly from that in the small intestine as a consequence of several physiological, physicochemical and biopharmaceutical factors (Corrigan, 1997; Fagerholm et al., 1997; Wilding, 2000; Schiller et al., 2005; Thombre, 2005; Sutton et al., 2006; Yang, 2008). 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 (Johannsson et al., xxxx; Abrahamsson et al., 1990). The applicability of the BCS for the colonic absorption of modified-release products has been extensively discussed (Corrigan, 1997; Wilding, 1999; Sutton et al., 2006). The consensus appears to be that drug absorption, when controlled by the intestinal permeability, is lower in the colonic tissue than in the small intestine because of the smaller surface area and tighter junctions of the epithelial cell layer in the former. There have not been any direct measurements of in vivo colonic Peff in humans to date. A few totalcolon perfusion studies have been performed, but these take 1– 3 days to position the tube into the cecum. Usually, the perfusion solution is collected via a rectal catheter inserted 5–10 cm above the anal verge (Devroede and Phillips, 1969; Mekjian et al., 1971). These perfusion experiments of the colon have not investigated drug transport but are instead physiological or pathophysiological studies. In contrast, a single-pass rectal perfusion based on a doubleballoon technique has been used in a couple of clinical studies. The rectal Peff values for phenoxymethylpenicillin, antipyrine and caprate were determined in human volunteers (Lennernas et al., 1995, 2002a). The human jejunal Peff was 4.3 times higher than the rectal Peff for antipyrine (5.6  104 cm/s vs 1.3  104 cm/s, respectively). The most plausible explanation for this 4-fold difference in the permeability of the jejunum and the rectum to antipyrine, a drug that is classified as having a high Peff and that is transported by passive transcellular diffusion, is that the available surface area of the epithelium is larger in the jejunum than in the rectum. These results agree with data derived from a jejunal perfusion study involving amoxicillin, using the double-balloon method. The jejunal Peff of amoxicillin was approximately 0.4  104 cm/s, which classifies it as a drug with a low intestinal Peff (Lennernas et al., 2002b). In another GI intubation study in which amoxicillin was given as a solution, absorption was higher from all sites in the small intestine than from the colon (Barr et al., 1994). The epithelial surface area factor and the absence of any uptake transporter in the colon are probably responsible for changes in the absorption of amoxicillin along the intestine. A recent regional absorption study in humans (i.e. bolus dosing of a solution both orally and directly into the colon and comparison of the drug absorption properties from plasma PK values) showed

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Intestinal site and perfusion method Fig. 2. The effective permeation (Peff) of 5 drugs from different BCS classes through human jejunum and ileum were compared in vivo (Schedl and Clifton, 1963; Schedl, 1965; Schedl et al., 1968; Gramatte, 1994; Gramatte et al., 1994, 1996; Gramatte and Richter, 1994; Lennernas, 1998). The absorption data were obtained using two single-pass perfusion tubes. One was situated in a segment perfused between two balloons and one was used in an open perfusion system.

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Fig. 3. (a and b) The relationship between in vivo effective permeation (Peff) through the human jejunum and in vitro results from Caco-2 studies (Lennernas et al., 1996) for drugs with low (Fig. 3a) and high (Fig. 3b) Peff, respectively.

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that 42 BCS class I drugs were well absorbed from the colon (Frelcolon > 70%) (Tannergren et al., 2009). The lower Peff drugs (BCS class III/IV) were absorbed less well from the colon (Frel-colon < 50%) than after oral dosing. Interestingly, there was a clear correlation between in vitro Caco-2 permeability and Frel-colon values, which is in agreement with the observation that Caco-2 is a better transport model for the large intestine than the small intestine. Data generated by Tannergren et al. in 2009 support the notion that atenolol and metoprolol could function as Peff markers for low and high colonic absorption, respectively. P-gp appeared to have no obvious effect on the colonic absorption of the investigated drugs (Tannergren et al., 2009), which adds weight to other studies indicating that the role of intestinal P-gp is over-rated (Lee et al., xxxx; Chiou et al., 2001). Based on this study and a recent PBPK study that used novel gastrointestinal absorption simulator software (GI-SIM), it was concluded that in silico predictions of absorption need to have access to better in vivo data for estimating regional intestinal Peff to encourage more rational development of modified-release dosage forms (Sjogren et al., xxxx; Tannergren et al., 2009). Mechanistic physiologically based modeling of GI absorption requires that input parameters such as regional intestinal permeability need to be accurate in order to be accepted as a rational tool in future dosage form design and development.

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The in vitro and in vivo correlation (IVIVC) between the results of different in vitro or in situ animal models and human in vivo Peff values is a crucial step in predicting GI drug absorption (Larregieu and Benet, xxxx; Fagerholm et al., 1996; Lennernas et al., 1996, 1997b; Winiwarter et al., 1998; Sun et al., 2002; Dahan and Amidon, 2009; Dahan et al., 2009b; Larregieu and Benet, 2013). It has been reported and discussed earlier that the absorption results for drugs transported by carrier-mediated mechanisms and/or via the paracellular route in the small intestine are not well correlated between Caco-2 monolayers and human intestine in vivo (Lennernas et al., 1996; Sun et al., 2002; Lennernas, 2007a). In studies carried out in a well established laboratory, the permeability coefficients of terbutaline and atenolol, two poorly permeating (BCS class III) drugs transported by slow passive diffusion, were 79- and 27-fold higher, respectively, in human jejunum in vivo than in Caco-2 cells in vitro (Fig. 3a) (Lennernas et al., 1996). In contrast, the permeability values for drugs such as antipyrine, naproxen and metoprolol that have an fa of >85% and are classified as permeating well (high Peff drugs) across the intestinal barrier were comparable for the two permeability models, as shown in Fig. 3b (Lennernas et al., 1996). In a later study, the IVIVC for drug permeability values was good for passively absorbed drugs (R2 = 85%) (Sun et al., 2002). These small differences for BCS class I and II drugs, when passive diffusion is the dominating transport mechanism, are also supported by the 4-fold difference between human jejunal and rectal in vivo Peff values for antipyrine (Lennernas et al., 1995). The carrier-mediated transport rates of L-dopa, L-leucine and D-glucose were also 34- to 1000-fold higher in human jejunum than in Caco-2 cells (Lennernas et al., 1996). Sun and coworkers also reported that the permeation of drugs transported by a carrier in humans was 3- to 35-fold higher than that of passively transported drugs. This observation agreed with the 2- to 595-fold differences in gene expression levels between Caco-2 cells and the human duodenum (Sun et al., 2002). The observed differences in gene expression levels were consistent with observed differences in carrier-mediated drug permeation. The poorer permeation of compounds transported by a carrier and of BCS class III and IV drugs is consistent with the colonic origin of Caco-2 cells. The results indicate that Caco-2 monolayers can be used to predict

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passive drug transport in humans, while prediction of transport by carrier-mediated systems may require a scaling factor because of the low expression of certain transport proteins in this cell line. These in vitro and other similar permeation data are significantly lower than in vivo proximal small intestinal Peff data and are therefore difficult to use in a PBPK-based absorption model without scaling (Larregieu and Benet, xxxx). However, in vitro permeability data from the Caco-2 model can directly predict whether a drug can be formulated as a modified-release dosage form with most of its absorption from the colon (Larregieu and Benet, xxxx; Lennernas et al., 1996; Lennernas, 2007b; Tannergren et al., 2009).

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Regional Peff for drugs can be determined in animal models, and especially the single-pass perfusion of the rat intestine is considered as a model for human intestinal transport with high predictive value (Incecayir et al., xxxx; Larregieu and Benet, xxxx; Sinko et al., 1991; Fagerholm et al., 1996; Fagerholm et al., 1997, 1999; Lennernas et al., 1997b; Chiou and Barve, 1998; Chiou et al., 2000; Lennernas, 2007a; Dahan and Amidon, 2009; Dahan et al., 2009a, 2009b). Small and large intestinal Peff have been measured using a single-pass perfusion approach in anaesthetized rats in situ at a single-pass perfusion flow rate of 0.2 ml/min, a 10-fold lower flow rate than that used in humans (Fagerholm and Lennernas, 1995; Fagerholm et al., 1996, 1997, 1999). The viability of the model assessed various physiological intestinal functions (Fagerholm et al., 1996). The rank order for passively transported drugs was similar in rat and humans, but the human in vivo Peff values were 3.8 times (R2; p < 000.5) higher than in situ in rats, irrespective of the BCS classification of the drug (Fagerholm et al., 1996). Other studies on the correlation between human and rat of intestinal absorption for drugs with various absorption routes has confirmed the results of Fagerholm et al. and Amidon et al. (Sinko et al., 1991; Fagerholm et al., 1996; Cao et al., 2006). A correlation between human and rat small intestine (R2 = 0.8) was observed for drug intestinal permeability driven both by carrier-mediated absorption and passive diffusion mechanisms (Cao et al., 2006). It has also been shown that there are no age related changes in passive and carrier-mediated absorption of drugs and nutrients (Lindahl et al., 1997). Although the small intestinal permeability data from the two species are highly correlated and while they have a similar transporter expression patterns, the expression levels and patterns for metabolizing enzymes in the intestine are quite distinct (Chiou and Barve, 1998; Chiou et al., 2001; Cao et al., 2006). A rat model, therefore, may be used to accurately predict oral drug absorption in the small intestine of humans, but not to predict drug metabolism or oral bioavailability (Chiou and Barve, 1998; Chiou et al., 2001; Cao et al., 2006; Lennernas, 2007a, 2007b, 2007c). The human and rat Peff have been demonstrated to predict the fraction of the oral dose absorbed in vivo in humans. Single-pass perfusion in the rat also provides permeability data that may be applied to classify drugs according to the biopharmaceutical classification system (Dahan et al., 2009a). A linear correlation (R2 = 0.975) for the fraction of the oral dose absorbed between humans and rats for 64 drugs has been reported (Chiou et al., 2000, 2001). All these evidence strongly support that the rat intestine is the best model to predict intestinal drug absorption in humans. Site-dependent intestinal permeability has been investigated using various clinical and non-clinical models as exemplified with data from 5 models drugs in Fig. 4 (Sjoberg et al., xxxx; Schedl, 1965; Gramatte et al., 1994; Fagerholm et al., 1997; Lennernas, 1998; Lindahl et al., 1998; Ungell et al., 1998; Nejdfors et al., 2000a, 2000b; Berggren et al., 2003; Dahan et al., 2009b). It is shown that the in situ rat Peff is decreasing in more distal intestinal

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indicate that rat intestine serves well as a transport model for prediction of human intestinal permeability and absorption, and that further studies are needed to better understand the regional differences in Peff in in vivo and in vitro models applied in biopharmaceutics research and drug development.

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There is a need for more exploratory in vivo studies to clarify regional drug absorption along the intestine, and especially from the colon. Development of experimental and theoretical in silico methods that predict absorption from both the small and large intestine is particularly encouraged. Development of these models requires assessment of the Peff of drugs from distal parts of the GI tract in humans. There is a trend for in vivo human jejunal Peff determinations obtained using open, single-pass perfusion methods to be slightly higher than the corresponding jejunal Peff-values determined using the double-balloon approach, irrespective of the BCS class of the drug. This could be explained by these open, singlepass perfusion models having different hydrodynamic conditions, a higher perfusion rate, or lower recovery of the perfusion solution leaving the test segment, or it could be that it is more difficult to monitor absorption conditions such as pH and osmolality with open models. However, it is possible to adjust for these rather small differences by accurately designing the absorption conditions. Many permeation data have also clearly demonstrated that the results of open perfusion Peff studies in the human jejunum agree largely with those obtained using the double-balloon approach. Increasing the availability of regional in vivo drug permeation data would stimulate the development of more relevant and complex in vitro absorption models, and form the basis for accurate PBPK-based modeling of GI drug absorption. It is crucial to accurately determine the input parameters in these theoretical models in order to increase acceptance of the models and simulation of GI drug absorption in general.

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Permeation of drugs in different models Fig. 4. Regional small and large intestinal in vitro and in vivo permeation of five model compounds in various in vivo and in vitro intestinal absorption models (Sjoberg et al., xxxx; Schedl, 1965; Gramatte et al., 1994; Fagerholm et al., 1997; Lennernas, 1998; Lindahl et al., 1998; Ungell et al., 1998; Nejdfors et al., 2000a, 2000b; Berggren et al., 2003; Dahan et al., 2009b).

Regional drug permeation in jejunum and colon - determined from human and rat tissue speciemn in the Ussing chamber model ( in vitro )

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segments for drugs that are transported by passive diffusion regardless of the BCS class (Fairstein et al., xxxx; Fagerholm et al., 1997; Lindahl et al., 1998). These observations agree with in vivo data from human intubation studies (Tannergren et al., 2009). Animal tissues, predominantly from rats, are widely used in the Ussing chamber model (an in vitro transmucosal model) and comparisons to human in vivo Peff have been reported (Lennernas et al., 1997b; Lennernas, 2007a). These in vitro transport data for drugs with low and high permeability are reduced and increased, respectively, in more distal human and rat intestinal specimens as demonstrated in Fig. 5 (Sjoberg et al., xxxx; Ungell et al., 1998; Berggren et al., 2003). The human and rat data in the various models displayed in Figs. 4 and 5 suggest a model difference between in vivo and in vitro and not a species difference. They also

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