Gastric emptying and small bowel water content after administration of

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Gastric emptying and small bowel water content after administration of grapefruit juice compared to water and iso-caloric solutions of glucose and fructose: a four-way crossover MRI pilot study in healthy subjects Michael Grimm, Mirko Koziolek, Marwa Saleh, Felix Schneider, Grzegorz Garbacz, Jens Peter Kuhn, and Werner Weitschies Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.7b00919 • Publication Date (Web): 03 Jan 2018 Downloaded from http://pubs.acs.org on January 5, 2018

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Molecular Pharmaceutics

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Gastric emptying and small bowel water content after administration of grapefruit

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juice compared to water and iso-caloric solutions of glucose and fructose:

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a four-way crossover MRI pilot study in healthy subjects

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Michael Grimm1, Mirko Koziolek1, Marwa Saleh1, Felix Schneider1, Grzegorz Garbacz2, Jens-

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Peter Kühn3,4 and Werner Weitschies1,*

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1

Institute of Pharmacy, Center of Drug Absorption and Transport, University of Greifswald, Germany

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2

Physiolution GmbH, Greifswald, Germany

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3

Institute of Radiology and Neuroradiology, University Medicine Greifswald, Germany

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4

Department of Radiology, University Medicine Dresden, Germany

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* Corresponding author:

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Prof. Dr. Werner Weitschies

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Institute of Pharmacy, Center of Drug Absorption and Transport

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Ernst Moritz Arndt University of Greifswald, Greifswald, Germany

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Felix-Hausdorff-Str. 3

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D-17487 Greifswald, Germany

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Tel +49 3834 420 4813

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[email protected]

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GRAPHICAL ABSTRACT

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2 ACS Paragon Plus Environment

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1

ABSTRACT

2

Grapefruit juice (GFJ) is known to affect the bioavailability of drugs in different ways. Despite the

3

influence on gastrointestinal enzymes and transporters, the influence on gastrointestinal fluid kinetics

4

is regarded to be relevant for the absorption of several drugs. Thus, it was the aim of this pilot study to

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investigate the gastric and intestinal volumes after intake of GFJ compared to isocaloric fructose and

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glucose solutions and water.

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The gastric and small intestinal volume kinetics after intake of 240 mL of GFJ, 10.6% fructose

8

solution, 10.6% glucose solution and water were investigated with magnetic resonance imaging in a

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four-way crossover study in six healthy human volunteers. The carbohydrate content of the

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administered beverages was quantified by HPLC. Even with the small sample size of this pilot study,

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the gastric emptying of GFJ and the glucose solution was significantly slower than that of water. The

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fructose solution had only a slightly delayed gastric emptying. Small bowel water content was

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increased by administration of GFJ and fructose solution, whereas it was decreased by glucose

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compared to the administration of pure water. At 80 min the small bowel water content after GFJ was

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twice as high as the small bowel water content after administration of water.

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The observed influence of GFJ on gastrointestinal fluid kinetics may explain certain phenomena in

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drugs pharmacokinetics. The effect is double edged, as the slower gastric emptying and increased

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intestinal filling can lead to enhanced or altered absorption. Due to the comparability of fruit juices, a

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general effect of fruit juices on gastrointestinal volumes is likely.

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KEY WORDS

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Grapefruit juice, Small intestine, stomach and duodenum, clinical pharmacology, gastric emptying,

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malabsorption, radiology/imaging, secretion/absorption



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INTRODUCTION

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The effect of grapefruit juice (GFJ) on the bioavailability of drugs is a phenomenon that has been

3

investigated for more than 25 years now. First studies reported interactions between the administration

4

of GFJ and certain cardiovascular drugs such as dihydropyridine calcium channel blockers

5

Nowadays, thanks to the intensive efforts of many researchers, it is known that the bioavailability of

6

drugs from various substance classes is affected by the co-administration of GFJ.

7

Typically, the interaction of GFJ with the pharmacokinetics of orally administered drugs is explained

8

by the inhibition of intestinal proteins, which includes metabolizing enzymes such as the cytochromes

9

P450 (CYP) or transporters such as the organic anion transporting polypeptide (OATP)

4–6

1–3

.

. For

10

instance, the inhibition of the intestinal CYP3A metabolism leads to an increased bioavailability as

11

was shown for various compounds

12

the direct inhibition of OATP1A2 as was demonstrated recently for fexofenadine or talinolol

13

Although discussed controversially in literature, the inhibition of intestinal efflux transporters like

14

pg-p is also regarded as relevant for the occurrence of positive effects on bioavailability 10,12.

15

These inhibitory effects of GFJ are generally associated with the presence of flavonoids 13,14 and thus,

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these effects are not limited to GFJ alone. Several other fruit juices (e.g. orange or apple juice) can

17

affect the pharmacokinetic profile of orally administered drugs in an equal way 5,11. By taking a closer

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look, this fact seems to be surprising as the amount of substances, which are assumed to have

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inhibitory effects, varies strongly and sometimes do not reach relevant concentrations in some of these

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juices 15. Moreover, for some compounds such as quercetin, the inhibitory effects that were shown in

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vitro could not be confirmed in vivo 16. In other studies, the presence of flavonoids such naringin or

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6’,7’-dihydroxybergamottin alone did not contribute to the effect of GFJ on the pharmacokinetics of

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nisoldipine, talinolol or cyclosporine

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behind the pronounced effect of GFJ on the pharmacokinetic profile of felodipine 19. In case of

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midazolam, the administration together with normal GFJ and GFJ of hybrid fruits with low

26

furanocumarin content does not affect the bioavailability 20. The results of these studies demonstrated

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that the common explanations for the effect of GFJ on the PK profile of orally administered drugs are

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not always valid. Thus, additional investigations are necessary to elucidate if the flavonoids are really

7–10

. In contrast, a reduced oral bioavailability can be the result of

2,17,18

11

.

. Moreover, the inhibition of CYP3A4 was not the reason


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responsible for the effect of GFJ as was turned out by Mouly and colleagues in a recent review

2

Interestingly, many drugs that are affected by the co-administration of fruit juices are also affected by

3

the co-administration of food. For instance, itraconazole shows an increase in bioavailability of nearly

4

20% when administered together with GFJ 22. With concomitant food intake and thus, more calories,

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the oral bioavailability is increased by 70% in comparison to fasted state intake 23. Positive effects of

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calorie intake as well as GFJ were also observed for blonanserin

7

administration of GFJ reduces the oral bioavailability by 61%, whereas the co-administration of food

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leads to a decrease of up to 70%

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pirfenidone 27–32.

25,26

24

.

. In case of aliskiren, the co-

. Similar trends were also observed for talinolol, acebutolol and

10

These examples strongly indicate that the caloric content of the fruit juices should be considered as

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well. In general, the caloric content is comparable for the different juices and amounts to 40-50 kcal

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per 100 g 15. Analogous to food, the administration of caloric liquids has various consequences for

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human GI function such as stimulation of bile secretion and delayed gastric emptying. For certain

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compounds, especially of BCS Class I such as paracetamol, gastric emptying even represents the rate

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limiting step for drug absorption from the small intestine 33,34. Recent studies have shown that gastric

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emptying is mainly dominated by calories and typically, gastric emptying rates of 2-4 kcal/min are

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reported in literature. In contrast to solid foods, the gastric emptying of caloric liquids follows first

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order kinetics

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typically controlled by caloric density, there are several examples of specific chemical entities like

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carbohydrates, amino acids or fatty acids directly influencing the gastric emptying

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behavior of fruit juices, the different effect of fructose and glucose on gastric emptying is regarded

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most important, as it is known that a glucose solution decreases gastric emptying much more

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pronounced than an isocaloric fructose solution does 40,42.

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Moreover, it should be noted that fruit juices are typically rich in fructose. From a physiological point

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of view, the presence fructose in the gut has other effects than glucose. This can be explained by the

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fact that glucose only can be registered by receptors in the small intestine. In a recent MRI study,

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Murray and colleagues observed that fructose increased and glucose decreased the small intestinal

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water content dramatically. They suggested that this effect was not only caused by gastric emptying,

35,36

. Although the gastric emptying of caloric compounds like foods and beverages is

35,37–41

. For the



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but also by intestinal phenomena 42. As some ripe fruits and their juices contain relevant amounts of

2

the sugar alcohol sorbitol, it should be further noted that sorbitol is known to affect small intestinal

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volumes strongly too 42,43.

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Apart from changed physicochemical conditions in the upper GI tract and delayed gastric emptying,

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the distribution of fluids in the fed human GI tract is regarded as one of the main reasons for the

6

occurrence of food effects

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volumes after food intake can enhance drug dissolution in the stomach and thus, increase oral

8

bioavailability. On the other hand, the absorption of compounds with limited permeability may depend

9

on the fluid volume in the small intestine. For instance, it was shown recently that the absorption of

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calcitonin is directly affected by the co-administered fluid volume 47. This effect may be explained by

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lower luminal drug concentration as a consequence of the increased fluid volume and thus, the

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concentration gradient between lumen and plasma is decreased. Additionally, increased volume also

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affects both, the total amount of the drug dissolved and dissolution rate of a drug as it increases the

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difference between actual and saturation concentration.

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In summary, it was hypothesized that the inhibition of enzymes and transporters by certain

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constituents of grapefruit juice is not the only reason for altered pharmacokinetic profiles after oral

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administration of certain drugs together with grapefruit juice. Due to the caloric value of GFJ, which is

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mainly caused by high concentration of sugars, we expected a substantial effect on luminal fluid

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volumes in stomach and small bowel as well as altered GI fluid kinetics. Thus, it was the aim of the

20

present pilot study to investigate the effect of GFJ on the fluid distribution in the human GI tract of

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healthy volunteers in comparison to the administration of the same volume of water. For this purpose,

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magnetic resonance imaging (MRI) was used to study the fluid volumes in stomach and small intestine

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as this imaging was already proven to be a suitable method for the investigation of gastrointestinal

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content volumes

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elaborate, can be estimated. The secondary aim of this study was to investigate the effect of fructose

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and glucose on luminal fluid volumes, with the same calories like the GFJ and thus with a lower

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caloric intake compared to the study by Murray and colleagues 42. Therefore, solutions of fructose and

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glucose equicaloric to GFJ were administered in two additional study arms. In order to estimate the

41,42,48–51

44–46

. In case of poorly water soluble compounds, increased gastric content

. This way, the usefulness of subsequent PK studies, which are much more


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likelihood of a carbohydrate dependent effect on GI fluid distribution for other fruit juices, the

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carbohydrate compositions of GFJ, orange juice and apple juice were compared with the aid of HPLC.

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MATERIALS & METHODS

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Ethics

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This imaging study was conducted in accordance with Good Clinical Practice Guidelines and

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Declaration of Helsinki. The study was performed according to German MPG §23b and procedures

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were approved by the ethical review board of the Ernst Moritz Arndt University of Greifswald,

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Germany (ethical protocol no. BB 079/14). Written informed consent was obtained for study

9

participation including MRI. Furthermore, the subjects received an appropriate expense allowance and

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were insured against any harm from study procedures.

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Subjects

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The clinical investigation was conducted with six healthy human volunteers (3 male / 3 female) with a

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mean age of 25.2 years (23 – 29 years) and a mean BMI of 23.4 kg/m² (22.2 – 25.0 kg/m²). They were

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ascertained to be in good health by means of histories and physical examinations. The subjects took no

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medications (except hormonal contraceptives) and abstained from alcohol during the study.

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Study protocol

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This prospective MRI study was carried out as a single center, 4-way cross over with no specific

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wash-out phase between the study days. The treatment order was randomized and subjects were not

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blinded for study procedure. An overnight fasting period of at least 10 h was performed before fluid

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administration. Each day only one subject was examined. Prior to fluid intake, the subjects underwent

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MR imaging to confirm fasted state and to quantify the resting volume in stomach and small intestine.

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The volunteers received 240 mL of four different beverages in upright position: (A) 100% Grapefuit

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juice (RAUCH Fruchtsäfte GmbH&CoOG, Austria), (B) 10.6% fructose solution (FAGRON

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GmbH&Co., Germany), (C) 10.6% glucose solution (FAGRON GmbH&Co., Germany) and (D) still

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mineral water (REWE Markt GmbH, Germany). The composition, osmolality and the caloric values of

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the fluids are given in Table 1. Osmolality was measured by freezing point depression with a semi-

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micro osmometer K-7400 (Knauer Wissenschaftliche Geräte GmbH, Germany). The beginning of the



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intake of the drinks was defined as t = 0 min. The subjects had to finish fluid administration within

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1 min.

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Table 1. Administered beverages and their composition in the four study treatments.

Treatment

Composition

Osmolality

pH

Calories per 240 mL

A

100% grapefruit juice

554 mOsmol/kg

3.3

103 kcal

B

10.6% fructose solution (59 mM)

641 mOsmol/kg

7.8

102 kcal

C

10.6% glucose solution (59 mM)

644 mOsmol/kg

7.8

102 kcal

D

still mineral water

5 mOsmol/kg

7.8

0 kcal

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The subjects were investigated by MRI at -1 min, 4 min, 9 min, 14 min, 19 min, 24 min, 29 min,

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34 min, 44 min, 54 min, 64 min, 74 min, 79 min and 94 min.

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Magnetic Resonance Imaging

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The imaging was performed using a commercially available Siemens MAGNETOM Aera MR scanner

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(Siemens Healthcare, Erlangen, Germany) with a field strength of 1.5 T, which was located at the

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Institute of Diagnostic Radiology and Neuroradiology, Greifswald. For the investigation of

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gastrointestinal fluid distribution, a strongly T2-weighted Half fourier-acquired Single-shot Turbo

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spin-echo (HASTE) sequence was chosen. As water appeared bright in these sequences due to its long

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T2 relaxation time, the volumes of stomach and small intestine could be easily delimited from

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surrounding tissues. The MR imaging parameters that were applied in this study are listed in Table 2.

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Table 2. Selected parameters of the T2-weighted HASTE MRI sequence used for imaging of gastrointestinal fluid volumes

Imaging Parameters

Value

Repetition time (TR)

1300 ms

Echo time (TE)

321 ms

Slice thickness

5.1 mm

Number of slices / orientation

40 / coronal

Interslice gap

0.77 mm

Matrix

256 x 256

Voxel size

1.76 x 1.76 x 5.1 mm³ ≈ 0.16 mL

Flip angle

160 °

17 18


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The subjects were positioned in head first, supine position for the whole imaging time. For signal

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detection, four desk-integrated spine coils and a six-element phase array abdominal receiver coil were

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used. To minimize movement artifacts all imaging procedures were performed within inspiration

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breath-hold commands.

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Image Analysis

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The images were analyzed using OsiriX v.3.9 32-bit (Pixmeo Sarl, Bernex, Switzerland). Similar to

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the work published by Schiller and colleagues 48, regions of high signal intensity (SI) were regarded as

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watery fluid and thus, they were marked automatically by an integrated software tool by using a lower

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threshold that was individually defined by internal calibrators under consideration of cerebrospinal

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fluid and gallbladder (Figure 1). Despite rarely occurring artifacts, the voxels with the highest SI in

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whole scanned volume represented free water. The threshold was typically defined to 30% to 40% of

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the SI value of the 99.9% quartile of brightest voxels in all slices. The SI of these brightest 0.1% of all

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voxels was furthermore most often the SI in the center of watery filled markings. The threshold

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needed to be adapted manually in this range to obtain a visually quantitative demarcation of

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compartments completely filled with liquid (e.g. gallbladder or stomach). As the subjects were not

16

placed inside the MRI scanner for administration of fluids, a new shimming process of the magnetic

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field had to be performed usually. Therefore, the SI changed and the threshold for watery fluids was

18

automatically adapted to the new contrast. If shimming was not necessary between two sequences, the

19

threshold was kept to assure comparability in between the time points.

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Areas marked by the software that did not belong to the gastrointestinal tract (e.g. gallbladder, urinary

21

bladder and kidneys) were erased manually. The watery pockets in colonic compartments were

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excluded from the evaluation as well. The fluid volumes of stomach and small intestine were

23

calculated subsequently using an integrated software tool based on the marked area in each slice as

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well as by considering the slice thickness and the interslice gap.

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Even after a 10 h overnight fasting period, the distal small intestine can be filled with a slurry of

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digested food, resulting in slightly grey zones, which is caused by their water content. These areas

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were not marked as free fluid volume due to their low SI, which was below the threshold. In contrast,

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free watery fluid pockets with higher SI inside these grey zones were included in the evaluation. 9 ACS Paragon Plus Environment


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Figure 1. Strongly T2-weighted images with marked stomach volume (left) and small intestinal volume (right) after administration of caloric beverages in two different subjects.

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Study Statistics

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The primary outcomes were the gastric emptying half-time (t1/2) representing the time point when 50%

6

of the ingested volume is emptied as well as the gastric and the small intestinal AUC. The t1/2 was

7

calculated from a first order fit, which was based on the natural logarithm (ln) of GCV. Therefore, the

8

ln (GCV) of each time point was calculated and the gastric emptying constant (ke) was obtained from

9

negative slope of the linear regression curve. For each subject, the time points included in the fit were

10

individually chosen until smallest GCV measured after intake of the beverages. t1/2 was calculated

11

from ke by using the equation t1/2 = ln2/ke.

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The AUCs were calculated by the trapezoidal rule from the volume curves. The data were tested for

13

normal distribution using the Kolmogorov-Smirnov test. The gastric emptying times t1/2 obtained in

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the different study arms were compared by using the non-parametric Friedman’s ANOVA with post-

15

hoc Dunn’s test.

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Differences in gastric volume AUC and small intestinal volume AUC, representing the volume

17

exposition in the gastrointestinal compartments between the four study procedures, were assessed

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using repeated measures one-way ANOVA with post-hoc Tukey’s Multiple Comparison Test due to

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normal distribution. Differences between male and female subjects were tested using the Mann-

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Whitney test. A p-value < 0.05 was considered to be statistically significant. All statistical evaluations 10 ACS Paragon Plus Environment

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1

were performed with GraphPad Prism 5 (GraphPad Software, Inc., USA). Graphical depictions were

2

prepared with OriginPro 8.5.1.G (OriginLab Corp., USA).

3

Carbohydrate Quantification of the beverages

4

Grapefruit, orange and apple 100% juice (RAUCH Fruchtsäfte GmbH&CoOG, Austria) and both

5

carbohydrate solutions from the human study were analyzed for their carbohydrate composition. The

6

determination of saccharose, glucose, fructose and sorbitol content was performed with HPLC coupled

7

with refractive index (RI) detection. An ELITE LaCrom HPLC System (Hitachi High Technologies

8

America, Inc., USA) equipped with a Bio-Rad HPX 87C Carbohydrate Analysis column, a Bio-Rad

9

Carbo C guard column and a Supelco 0.22 µm inline-filter was used for carbohydrate analysis.

10

For investigations of the juices and the corresponding standards, a LiChrospher 100 RP18 (5 µm) as

11

second pre-column was inserted in front of the normal guard column to minimize disturbing peaks by

12

possible interfering juice ingredients. For all investigations, the mobile phase was pure HPLC

13

millipore water (conductivity < 5 µS/cm). Separation was performed at a column temperature of 40 °C

14

with a flow rate of 0.6 mL/min. The RI detection had a measuring rate of 1.25 Hz with a detector cell

15

temperature of 30 °C ± 1 °C. The dynamic range of the detector was 0.4 RI units.

16

Injection volumes of 2 µL, 5 µL and 10 µL were used with constant values in every measurement

17

series. Changing the injection volumes offered the opportunity to adjust the amount of analyzed

18

substance on the column in order to meet the dynamic range of the detector. The HPLC method used

19

in this study allowed the baseline separation of the analytes saccharose, glucose, fructose and sorbitol.

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Page 12 of 42

1

RESULTS

2

The study procedures were well tolerated by all included volunteers and no adverse events could be

3

observed. In one case, study procedure A (administration of GFJ) was discontinued after fasted state

4

imaging prior administration, due to residual food components still present in the stomach after the

5

overnight fast of 10 h. The subject provided additional consent for repetition of the study procedures

6

and hence, the measurements were repeated on another day. The applied T2-weighted sequences were

7

suitable for the calculation of gastric and small intestinal volumes in all subjects.

8 9 10

Figure 2. Mean volumes +/- SD of gastric content volume (left) and small bowel water content (right) after administration of 240 mL GFJ, fructose solution, glucose solution and water (n=6).

11 12

Gastric fluid volumes

13

The mean curves of the fluid volumes in stomach and small intestine of all four study arms are given

14

in Figure 2. Except for the aforementioned case, homogeneous hyperintense areas were observed in all

15

slices of the fasted stomach, indicating the presence of secretions only. The gastric fasted resting

16

volumes amounted to 23 ± 36 mL, 24 ± 19 mL, 17 ± 12 mL and 26 ± 24 mL before administration of

17

GFJ, fructose solution, glucose solution and water, respectively.


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1 2 3 4

Figure 3. Individual profiles of gastric content volumes (GCV) after administration of 240 mL GFJ, fructose solution, glucose solution and water, with male subjects marked in black and female subjects marked in grey (n=6).

5 6

In Figure 3, all individual gastric fluid volume curves are depicted. It can be seen, that the gastric

7

emptying of water and glucose solution was reproducible with less pronounced interindividual

8

variability, whereas the variability after administration of GFJ and fructose solution was higher. From

9

these curves, gastric emptying t1/2 and AUCs were obtained. The correlation coefficient for the fit on

10

the natural logarithm of GCV was always good with mean R2 (A) = 0.94 ± 0.06, R2 (B) = 0.94 ± 0.05,

11

R2 (C) = 0.93 ± 0.04 and R2 (D) = 0.95 ± 0.03. In all cases the female subjects tended to have a slower

12

gastric emptying, but the small sample size in this pilot study limits evaluation. The half gastric

13

emptying times (t1/2) obtained for each study treatment are compared in Figure 4.



1 2 3 4

Page 14 of 42

Figure 4. Boxplots of Gastric emptying half-times t1/2 for the volume decrease after administration of 240 mL GFJ, fructose solution, glucose solution and water (n=6, Whisker 0-100%). * significant difference checked by Friedmann’s test with Dunn’s post-test (p

Gastric emptying and small bowel water content after administration of

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