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https://doi.org/10.5599/admet.2454

Food and bile micelle binding of zwitterionic antihistamine drugs

Rie Takeuchi
Kiyohiko Sugano


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Abstract
Background and purpose
The food effects on oral drug absorption are challenging to predict from in vitro data. Food intake has been reported to reduce the oral absorption of several zwitterionic antihistamine drugs. However, the mechanism for this negative food effect has not been clear. The purpose of the present study was to evaluate the bile micelle and food binding of zwitterionic antihistamine drugs as a possible mechanism for the negative food effects on their oral drug absorption.
Experimental approach
Bilastine (BIL), cetirizine (CET), fexofenadine (FEX), and olopatadine (OLO) were employed as model drugs. The fed/fasted AUC ratios of BIL, CET, FEX, and OLO after oral administration are reported to be 0.60 to 0.7, 0.92, 0.76 to 0.85, and 0.84, respectively. The unbound fraction (fu) of these drugs in the fasted and fed state simulated intestinal fluids (FaSSIF and FeSSIF, containing 3 and 15 mM taurocholic acid, respectively) with or without FDA breakfast homogenate (BFH) was measured by dynamic dialysis.
Key results
The FeSSIF/ FaSSIF fu ratios were 0.90 (BIL), 0.46 (CET), 0.76 (FEX), and 0.78 (OLO). In the presence of BFH, the fu ratios were reduced to 0.52 (BIL), 0.22 (CET), 0.39 (FEX), and 0.44 (OLO).
Conclusion
Despite being zwitterion at pH 6.5, the antihistamine drugs were bound to bile micelles. Bile micelle and food binding were suggested to cause a negative food effect on the oral absorption of these drugs. However, the AUC ratio was not quantitatively predicted by using FeSSIF + BFH.

Ključne riječi

Negative food effect; unbound fraction; simulated intestinal fluid; dynamic dialysis; intestinal membrane permeation; zwitterionic; antihistamine

Hrčak ID:

321848

URI

https://hrcak.srce.hr/321848

Datum izdavanja:

1.11.2024.

Posjeta: 20 *




Introduction

The oral absorption of a drug is affected by various physiological factors in the gastrointestinal tract [1]. The physiological conditions in the fed state are markedly different from those in the fasted state. For example, bile micelle concentration is significantly increased in the fed state. In addition, food components can interact with drug molecules. It is still challenging to predict the food effects on oral drug absorption from in vitro data [2-4]. In the mechanistic oral absorption models, the free (unbound) fraction in the intestinal fluid (fu) is one of the key parameters that determine the effective intestinal permeability of a drug (Peff) [5]. High solubility/ low permeability drugs tend to show a negative food effect. In these cases, the rate and extent of fraction dose absorbed Fa is limited by epithelial membrane permeation (Fa rate-limiting step (FaRLS): permeability-limited (PL) by the epithelial membrane (PL-E)) [2,6]. Recently, the bile micelle and food binding of drugs were reported to be able to elucidate the negative food effect for hydrophilic tertiary and quaternary amines [5,7]. Some zwitterionic antihistamine drugs are also known to show negative food effects in humans. However, it has not been clear whether a zwitterionic drug can also bind to bile micelles and/or food components.

The purpose of the present study was to investigate whether zwitterionic antihistamine drugs can bind to bile micelles and food components. Bilastine (BIL), cetirizine (CET), fexofenadine (FEX), and olopatadine (OLO) were employed as model drugs (Figure 1). The physicochemical properties of these drugs are shown inTable 1. These drugs are zwitterionic and show moderate lipophilicity at pH 6.5. The fed/fasted AUC ratios of BIL, CET, FEX, and OLO are 0.60 to 0.7 [8-10], 0.92 [11], 0.76 to 0.85 [12,13], and 0.84 [14], respectively. In this study, dynamic dialysis was used to measure the fu values in the simulated intestinal fluids consisting of bile micelles and food homogenates.

Figure 1. Chemical structures of zwitterionic antihistamine model drugs
ADMET-12-2454-g001.jpg
Table 1. Physicochemical properties and clinical data of model drugs
DrugMWpKa aIsoelectric pointlog Doct pH 6.5bDose, mgFood effect, %c
Bilastine4644.0 (A)
8.8 (B)
6.400.39 ± 0.01200.60 – 0.70
Cetirizine3892.12 (B)
2.90 (A)
7.98 (B)
5.441.46 ± 0.01100.92
Fexofenadine5024.20 (A)
7.84 (B)
6.020.51 ± 0.011200.76 – 0.85
Olopatadine3374.18 (A)
9.79 (B)
6.990.34 ± 0.01100.84

[i] a Bilastine (estimated from the pH - log Doct profile. Temperature and ionic strength not reported) [8], cetirizine (25 ˚C, I = 0.15 M) [15], fexofenadine (24 ˚C, I = 0.01 M) [15], and olopatadine (Temperature and ionic strength not reported) [14].

[ii] b Measured in this study

[iii] c AUC ratio (fed/fasted). Bilastine [8], cetirizine [11], fexofenadine [12] and olopatadine [14].

The permeation flux (J) is expressed by the total drug concentration dissolved in the GI fluid (Cdissolv = unbound + bound) and the effective (apparent) permeation coefficient (Peff) as inEquation (1) [2]:

(1)
ADMET-12-2454-e001.jpg

In the case of PL-E, according to the free fraction theory, only unbound molecules can permeate the epithelial membrane,Equation (2),

(2)
ADMET-12-2454-e002.jpg

where Pep is the epithelial membrane permeation coefficient defined based on the unbound drug concentration, and fu is the unbound (free) fraction. Bile micelle and food binding can reduce the concentration of unbound drug molecules (= fu Cdissolv) at the epithelial membrane surface. In the case when the oral absorption of a drug is permeability-limited, Fa can be calculated as inEquation (3)

(3)
ADMET-12-2454-e003.jpg

where A = 1.4 × 104 s/cm (Peff in cm/s). The Fa ratio (= AUC ratio) in the fasted/fed states approximately becomes the fu ratio (fu,fed/fu,fasted) for Fa < 0.7 cases [2].

Experimental

Material

Fexofenadine hydrochloride, bilastine, olopatadine hydrochloride, and cetirizine dihydrochloride were purchased from Tokyo Chemical Industry Co., Ltd (Tokyo, Japan). Sodium chloride (NaCl), sodium dihydrogen phosphate dihydrate (NaH2PO4 2H2O), 8N NaOH, 1-octanol, taurocholic acid (TC), and oleic acid (OA) were purchased from FUJIFILM Wako Pure Chemical Corporation (Osaka, Japan). Egg yolk lecithin (EL) was purchased from Kewpie Corporation (Tokyo, Japan). Glyceryl mono-oleate (GM) was purchased from Nippon Surfactant Industries Co., Ltd (Tokyo, Japan). A cellulose dialysis membrane (Φ 15.9×25 mm×15 m) was purchased from As-One Corporation (Osaka, Japan).

The FDA breakfast ingredients, and other food were purchased from the local market (bacon (Itoham Foods Inc, Japan), toast (Choujuku bread, Pasco Shikishima Corporation, Japan), egg (Akadama, miwa keien Co., Ltd, Japan), hash browns (Hoshino potato, Heinz Japan Ltd, Japan), whole milk (Oishii Megumilk Snow Brand Milk, MEGMILK SNOW BRAND Co., Ltd, Japan), butter (Hokkaido-butter, MEGMILK SNOW BRAND Co., Ltd, Japan).

Methods

Processing of FDA Breakfast

The FDA breakfast was comprised of one strip of bacon, half a slice of toast, one fried egg, 55 g of hash browns, 30 g of butter, and 100 mL of whole milk. After cooking, the FDA breakfast was homogenized for 15 s by a food processor. The FDA breakfast homogenate (BFH) was divided into small aliquots and stored in a freezer (-30 °C). It was thawed under running water before use.

Measurement of the unbound fraction by dynamic dialysis

Dynamic dialysis was performed using a side-by-side chamber (SANPLATEC Co., Ltd (Osaka, Japan)) with a cellulose dialysis membrane (molecular weight cut-off: 3500). The membrane area was 2.0 cm2. The fluid volume was 1.5 mL for both the donor and acceptor sides. The fasted and fed state simulated intestinal fluids (FaSSIF and FeSSIF, respectively) with or without BFH were used as test media (Table 2). Each drug was dissolved in the test media and added to the donor side (0.04 mM (BIL), 0.2 mM (CTZ), 0.5 mM (FEX), and 0.5 mM (OLO)). The blank FaSSIF was added to the acceptor side. After incubation for 1 h at 37 °C, the drug concentration in the acceptor side was measured by HPLC (Shimazu Prominence LC-20 series and Agilent Technologies 1200 Series, column: ZORBAX Eclipse Plus (C18 2.1×50 mm, 3.5 μm) (Agilent Technologies), flow rate: 0.6 mL min-1, mobile phase: 0.1 % trifluoroacetic acid-acetonitrile/0.1 % trifluoroacetic acid-water (25 % (BIL), 35 % (CTZ), 35 % (FEX), and 28 % (OLO)), detection: UV (BIL: 280 nm, CET: 230 nm, FEX: 225 nm, and OLO: 300 nm), column temperature: 40 °C, and injection volume of 10 μL).

Table 2. Composition of simulated intestinal fluids a
Test mediumContent, mMBFH, %c
TCELGMOA
FaSSIF30.75000
FeSSIF153.75000
×2FeSSIF307.50000
FeSSIFv2102.050.80
BFH b000050
FeSSIF+BFH153.750050

[i] a The components were dissolved in a phosphate buffer (phosphate 28.6 mM, NaCl 106 mM, pH 6.5) (blank FaSSIF). TC: taurocholic acid, EL: egg lecithin, GM: Glyceryl mono-oleate, OA: oleic acid.

[ii] b BFH added to blank FaSSIF.

[iii] c wt.%

Permeation was calculated as the ratio of the concentration in the acceptor side at 1 h and the theoretical equilibrium concentration (0.02 mM (BIL), 0.1 mM (CTZ), 0.25 mM (FEX), and 0.25 mM (OLO)) (×100 to convert to %). The unbound fraction (fu) was calculated as the ratio of permeation in each medium and the test medium of Blank FaSSIF.

The octanol-water distribution coefficient measurement

The octanol-water distribution coefficient (log Doct) values of model drugs were measured by the shake-flask method. A model drug was dissolved in blank FaSSIF pre-saturated with 1-octanol (BIL: 0.1 mM, CTZ: 1 mM, FEX: 1 mM, and OLO: 1 mM). The drug solution (2.5 mL or 5.5 mL) was added to 0.5 mL of 1-octanol pre-saturated with water. The samples were shaken by a shaker for 90 minutes at room temperature (25 ± 2 °C). The drug concentration in the aqueous phase was measured by a UV absorbance (BIL: 280 nm, CET: 230 nm, FEX: 225 nm, and OLO: 300 nm, UV-1850, Shimadzu Corporation, Kyoto, Japan). The log Doct value was calculated byEquation 4:

(4)
ADMET-12-2454-e004.jpg

where Caq,ini and Caq are the initial and equilibrium drug concentrations in the aqueous phase, and Vaq and Voct are the volume of aqueous and octanol phases, respectively.

Results and discussion

The fu values of all drugs decreased in the presence of bile micelles and BFH (Figure 2,Table 3). This result suggests that the reduction of fu by bile micelle binding in the fed state is likely to be one of the reasons for the negative food effect on the oral absorption of these drugs. The addition of BFH also decreased the fu values of model drugs. Therefore, direct food binding could also be one of the reasons for the negative food effect.

Figure 2. Effect of bile micelles and FDA breakfast homogenate (BFH) on the fu values of zwitterionic antihistamine drugs.
ADMET-12-2454-g002.jpg
Table 3. Permeation and fua
DrugTest mediumPermeation at 1 h, %fufu ratio b
BilastineBlank FaSSIF15.6 ± 0.5
FaSSIF17.3 ± 0.81.10 ± 0.05
FeSSIF15.5 ± 0.70.99 ± 0.050.90 ± 0.04
×2 FeSSIF12.1 ± 0.60.78 ± 0.040.70 ± 0.03
FeSSIF-V213.4 ± 0.80.86 ± 0.060.78 ± 0.05
BFH9.0 ± 0.10.58 ± 0.000.52 ± 0.00
FeSSIF+BFH9.0 ± 0.10.58 ± 0.010.52 ± 0.01
CetirizineBlank FaSSIF16.4 ± 0.6
FaSSIF16.3 ± 0.50.99 ± 0.03
FeSSIF7.4 ± 0.20.45 ± 0.010.46 ± 0.01
×2 FeSSIF3.8 ± 0.10.23 ± 0.010.23 ± 0.01
FeSSIF-V28.7 ± 0.10.53 ± 0.000.53 ± 0.00
BFH4.6 ± 0.00.28 ± 0.000.29 ± 0.00
FeSSIF+BFH3.5 ± 0.20.21 ± 0.010.22 ± 0.01
FexofenadineBlank FaSSIF12.0 ± 0.7
FaSSIF13.1 ± 0.51.09 ± 0.04
FeSSIF10.0 ± 0.70.84 ± 0.060.76 ± 0.06
×2 FeSSIF7.7 ± 0.60.64 ± 0.050.59 ± 0.05
FeSSIF-V210.6 ± 0.40.88 ± 0.030.81 ± 0.03
BFH5.4 ± 0.10.45 ± 0.010.41 ± 0.01
FeSSIF+BFH5.1 ± 0.10.43 ± 0.010.39 ± 0.01
OlopatadineBlank FaSSIF20.8 ± 0.7
FaSSIF21.9 ± 0.51.05 ± 0.02
FeSSIF17.1 ± 0.30.82 ± 0.020.78 ± 0.02
×2 FeSSIF12.2 ± 0.10.59 ± 0.010.56 ± 0.01
FeSSIF-V218.4 ± 0.30.88 ± 0.010.84 ± 0.01
BFH10.3 ± 0.30.50 ± 0.020.47 ± 0.01
FeSSIF+BFH9.7 ± 0.20.46 ± 0.010.44 ± 0.01

[i] aMean ± S.D., n = 3

[ii] bvs. the fu value in FaSSIF

The fu ratios of FeSSIF/FaSSIF of FEX and OLO were in good agreement with the extent of the food effect in humans. However, the food effect was underestimated for BIL and overestimated for CET. In the presence of BFH, the fu ratio of FeSSIF/FaSSIF of BIL was in good agreement with the food effect. Even though the fu ratio of CET is lower than that of the other drugs, the clinical negative food effect on the oral absorption of CET is less significant. This would be due to the higher lipophilicity and faster passive permeability of CET. In such case, the extent of Fa becomes less sensitive to a decrease in fu and Peff (Eq. 3). The bioavailability in humans of CET is > 70 % [11], which is higher than that of FEX (33 %) [16] and BIL (61 %) [8].

The charge species distribution of the model drugs is shown inFigure 3. Despite being zwitterion at pH 6.5, the antihistamine drugs were bound to bile micelles. The bile micelle binding of CET was stronger than that of others, as expected from its higher log Doct (CET > FEX ≈ BIL ≈ OLO). CET is a triprotic compound [17,18]. However, the first pKa (N1 of the piperidine group) is 2.12 and is not protonated at pH 6.5. Therefore, CET mainly exists as a zwitterion at pH 6.5.

Figure 3. Charge species distribution of zwitterionic antihistamine drugs
ADMET-12-2454-g003.jpg

The log Doct values of BIL (0.39) and OLO (0.34) are close to that of propranolol (PRO) (log Doct = 0.4) [5]. In addition, the amine groups of these drugs are > 99 % charged at pH 6.5. However, the bile micelle binding of propranolol is reported to be about 3-fold stronger than those of BIL and OLO. In addition, even though the log Doct values of the zwitterions are greater than that of quaternary ammonium compounds (QAC) (log Doct ≪ 0), the fu values of the zwitterionic drugs are comparable with that of QACs [7]. The bile micelles in FaSSIF and FeSSIF are negatively charged by the -SO3- group in taurocholic acid. Therefore, the carboxyl anion (-COO-) in the zwitterionic drugs was suggested to reduce the bile micelle binding, like in the cases of liposome binding [18,19]. In a buffer solution at the isoelectric pH point, a zwitterion drug exists as an equilibrium between a zwitterion molecule and an un-ionized molecule [20]. The isoelectric pH points of the model drugs are near pH 6.5 (5.4 to 7.0) (Table 1). From the difference between the pKa values of carboxylic acid and amine (> 3.6), they are estimated to exist as the zwitterion more than 99.8 % [21]. Therefore, the zwitterionic molecules may bind bile micelles. A more detailed mechanism of the charge effect on the bile micelle binding of drugs is under investigation.

Conclusions

In conclusion, the zwitterionic antihistamine drugs were found to bind to bile micelles and foods, suggesting that it would be the reason for the negative food effect. The lipophilicity and charge state were suggested to affect the bile micelle binding. Dynamic dialysis would be a good tool to measure bile micelle and food binding.

Notes

[9] Funding: No funding support

[10] Conflicts of interest Conflict of interest: The Author(s) declare(s) that they have no conflicts of interest to disclose.

[11] Author contributions: Material preparation, data collection and analysis were performed by Rie Takeuchi. Kiyohiko Sugano supervised all phases of the study, including the manuscript writing. All authors read and approved the final manuscript.

[12] Data availability: The datasets generated during and/or analysed during the current study are available from the corresponding author on request.

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