Evaluation of Absorption Kinetics of Orally Administered
Theophylline in Rats Based on Gastrointestinal Transit
Monitoring by Gamma Scintigraphy
SHUNJI HARUTA,1,2 KEIICHI KAWAI,3 SEISHI JINNOUCHI,4 KEN-ICHI OGAWARA,2 KAZUTAKA HIGAKI,2SHOZO TAMURA,4 KAZUHIKO ARIMORI,1 TOSHIKIRO KIMURA2
1

Department of Hospital Pharmacy, Central Research Laboratories, and Department of Radiology, Miyazaki Medical College,
5200 Kihara, Kiyotake-cho, Miyazaki 889-1692, Japan2

Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Okayama
700-8530, Japan

3

Central Research Laboratories, Miyazaki Medical College, 5200 Kihara, Kiyotake-cho, Miyazaki 889-1692, Japan

4

Department of Radiology, Miyazaki Medical College, 5200 Kihara, Kiyotake-cho, Miyazaki 889-1692, Japan

Received 31 Jaunary 2000; revised 28 September 2000; accepted 6 October 2000

ABSTRACT: The gastrointestinal (GI) transit and absorption of orally administeredtheophylline, a highly absorbable drug without presystemic elimination, were
investigated under fasted and fed conditions using three rats in a crossover study. To
evaluate the GI transit rate for each segment in vivo, a noninvasive technique, gamma
scintigraphy, was employed using a nonabsorbable compound, 99mTc-labeled diethylenetriamine pentaacetic acid (DTPA). Using a gamma scintigraphic technique it ispossible to simultaneously evaluate the GI transit and absorption of orally administereddrug in the same individual. Theophylline was simultaneously administered along with
[99mTc]DTPA to animals in the fasted and fed states. Each GI transit pattern, simulatedusing the GI transit±kinetic model with a lag time factor, was well ®tted to theexperimental data. Gastric emptying rate varied in each study, even under the same
experimental condition. The GI transit pattern for each segment was highly variable,
especially in animals in the fed state. This inconsistency in transit pattern was mainly
due to the variability in gastric emptying, which was much slower in animals in the fed
compared with the fasted state. However, in spite of a large variability of GI transit
kinetics, the plasma concentration±time curves of theophylline were well predicted by
the GI transit±absorption model using the individual GI transit parameters obtained in
the study. The absorption rate of theophylline was considerably reduced in animals in
the fed state, because of the reduction of gastric emptying rate. Analysis using GI
transit±absorption model and gamma scintigraphic technique made it possible toestimate the variable absorption kinetics regulated by GI transit with hugevariability. ß 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci
90:464±473, 2001
Keywords: oral absorption kinetics; gastrointestinal transit; gamma scintigraphy;

GI transit absorption model; theophylline

Correspondence to: T. Kimura (Telephone: 81-86-251-7948;
Fax: 81-86-251-7926;
E-mail: kimura@pheasant.pharm.okayama-u.ac.jp)
Journal of Pharmaceutical Sciences, Vol. 90, 464±473 (2001)
ß 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association

464

INTRODUCTION
The gastrointestinal (GI) absorption of orally
administered drugs is determined by two major
factors, the permeability of GI mucosa and the GI

JOURNAL OF PHARMACEUTICAL SCIENCE, VOL. 90, NO. 4, APRIL 2001

GAMMA SCINTIGRAPHIC EVALUATION OF GASTROINTESTINAL TRANSIT OF THEOPHYLLINE

transit rate. In particular, the GI transit rate isfrequently affected by various factors (e.g., individual difference,1 meals,2 disease states,3 etc.),
resulting in remarkable alteration of the absorption pro®le of orally administered drugs.
In our previous paper,4 a novel method basedon GI transit kinetics was developed for estimating the absorption pro®les of drugs administeredorally as an aqueous solution. The validity andthe utility of the prediction method were demonstrated for model drugs with different absorption
characteristics in rats under the fasted condition,using the GI transit rate constant for each segment along the GI tract that was obtained as
averaged values using phenol red as a nonabsorbable marker. However, to evaluate the drug
absorption kinetics, especially in animals in the
fed condition, the prediction of the plasma
concentration±time curve after oral administration should be performed using each individualtransit kinetics, because GI transit kinetics
including gastric emptying could show a large
intraindividual and/or interindividual variability
in animals in the fed state.5,6
In the present study, a noninvasive technique,gamma scintigraphy, was used to evaluate the GI
transit of orally administered drugs in rats. The
use of gamma scintigraphy to assess GI transit inexperimental and clinical practice has been wellestablished and utilized.7±14 Even in rats15 andcats,16 this method has already been applied to evaluate the gastric emptying pro®le. This techniqueallows simultaneous evaluation of G transit andoral absorbability of drug in the same individual.
As an absorbable drug without ®rst-pass elimination after oral administration,17 theophylline wasadministered along with 99mTc-labeled diethylenetriamine pentaacetic acid ([99mTc]DTPA) solution. The prediction of plasma concentration±
time curves for theophylline in each individual
was performed using both the GI transit rate
constant determined for each individual and theaveraged absorption rate constant for each segment. The predicted plasma concentration±time
curve was compared with the observed data in thesame individual, and the effect of food on theabsorption kinetics was also investigated.

EXPERIMENTAL SECTION
Materials
Aminophylline (Sigma Chemical Company, St.
Louis, MO) and theophylline (Tokyo Kasei Kogyo

465

Company, Tokyo, Japan) were obtained commercially. All chemicals and reagents were analyticalgrade commercial products. The 99mTc was obtained as sodium pertechnetate solution by elution ofa generator, and [99mTc]DTPA was prepared using
a kit containing calcium trisodium diethylenetriamine pentaacetate and stannous chloride dihydrate (Daiichi Radioisotope Lab., Tokyo, Japan).
Animals
Three male Wistar rats weighing 400±500 g(Kyudo Farm, Fukuoka, Japan) were fasted for
24 h prior to and during the experiment in thefasted study. In the case of the fed study, after
fasting for 24 h, rats were allowed free access tostandard laboratory chow (Clea Japan, Tokyo,
Japan) for 12 h just before starting the study. Ourinvestigation was performed after approval by our
local ethical committee at Miyazaki Medical
College and in accordance with ``Interdisciplinary
Principles and Guidelines of the Use of Animals in
Research''.
Gamma Scintigraphic Study
A gamma scintigraphy, noninvasive technique
was employed to measure GI transit rate for eachsegment with a gamma camera system (PRISM
3000-Odyssay, Picker International Inc., Cleveland, OH). An aqueous solution of [99mTc]DTPA,
a nonabsorbable compound,8 was prepared as a
tracer passing through GI tract. [99mTc]DTPA(0.4±0.5 mCi/body) was administered intragastrically to the rat using a gastric sonde with anabsorbable drug. The dosed rat was kept in a
restraining cage that was placed on the scintillation camera. The gamma scintigraphic imaging
started just after dosing and was carried out for
6 h at 2-min intervals under the dynamic planar
condition.
Determination of GI Transit Rate Constant for
Each Segment
GI tract was divided into four segments: stomach(s), jejunum (jej), ileum (ile), cecum and below (ce).
The region of interest (ROI) for each segment wasdetermined as follows. The ROIs of stomach andcecum were determined by the scintigraphic
images taken just after dosing and at the endof the experiments, respectively, because thoseimages showed almost the entire GI segment containing almost all the dosed [99mTc]DTPA. The
small intestine could be basically separated to the
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 90, NO. 4, APRIL 2001

466

HARUTA ET AL.

proximal half and distal half by drawing a horizontal line, which we de®ned as jejunal and ileal
segments, respectively. However, because thedemarcation for both segments is not clear, somecorrections were needed based on close examination of the [99mTc]DTPA locus using 120 images
taken during each whole study, as reported by
Digenis et al.13 The important point for thosecorrections is that the locus and transit directionof [99mTc]DTPA must be closely examinedthroughout the study and then the position of
the segment can be judged. The radioactivity ineach segment was then measured in each ROI,
and the images were analyzed by computer-aided
densitometry using the public domain National
Institute of Health (NIH) Image program (http://rsb. info.nih.gov/nihimage/). After correcting
the decay of gamma ray by using the half-life of99m
Tc (6.02 h), the relative percent of radioactivity
in each ROI was plotted against time. The GI
transit rate constant (ki) of each segment i foreach individual study was obtained by ®tting theexperimental GI transit data to the GI transit±
kinetic model4 with the nonlinear regression
program MULTI (FILT).18 In the present study,a lagtime factor in the ileocecal region was
introduced into the GI transit±kinetic model.
Determination of Absorption Rate Constantfor Each Segment
The absorption experiments were performed forthe jejunum and ileum by a conventional in situ
closed-loop method.19 The initial concentration ofaminophylline and the period of absorption experiment were 0.5 mg/mL and 5 min, respectively. The®rst-order absorption rate constant (kai) was estimated by the rate of disappearance of drug fromthe lumen. The averaged kai values of theophylline thus obtained for the jejunum and ileum,
which were cited in our previous paper,4 are
11.882 and 8.080 h ÿ 1, respectively. The values of
ka of stomach and colon were assumed to be zero
because no contribution from these segments tothe absorption of theophylline was shown in ourprevious studies.4,20
Oral and Intravenous Administration
For the oral administration study, the rightfemoral artery was cannulated with vinyl tubing(i.d., 0.5  0.8 mm; Dural Plastics and Engineering, Australia) while the animal was under ether
anesthesia. The solution of aminophylline (5 mg/5
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 90, NO. 4, APRIL 2001

mL/kg) was administered intragastrically to therat along with a GI transit marker, [99mTc]DTPA.
Blood samples were periodically taken from thecannulated femoral artery. The oral administration studies were performed with animals in
the fasted condition (fasted for 24 h prior to andduring the experiment, but allowed free access towater) and the fed condition after a recovery
period of 1 week in each rat.
For the intravenous (iv) administration study,aminophylline was administered as a solution bybolus injection (5 mg/5 mL/kg) into the left femoralvein, and blood samples were periodically takenfrom the cannulated right femoral artery. The
plasma concentration±time curve of theophylline
was analyzed by a two-compartment model. The
pharmacokinetic parameters were estimated by®tting the plasma concentration versus time
data after iv administration to a model equation
Cp  Aeÿat  Beÿbt .
Analytical Method
Theophylline in the plasma was determined by
the reversed-phase high-performance liquid chromatography (HPLC) method.21 Brie¯y, plasma
samples were deproteinized with acetonitrile.
After centrifugation at 3000 rpm for 10 min, thesupernatant of the mixture was injected onto the
HPLC system, which consisted of a high-performance liquid chromatograph (L-7100, Hitachi,
Tokyo) connected to an ODS column (SPHERISORB ODS-2-5 (250  4.6 mm) Chemco Scienti®cCompany, Tokyo) and an ultraviolet (UV) detector(L-7400, Hitachi). The mobile phase, ¯ow rate,
and wavelength of the detector were 5 mM acetate
buffer (pH 4.8): acetonitrile (9:1 by volume), 1.0
mL/min, and 272 nm, respectively.
Statistical Analysis
A student's paired t test was performed to estimate the signi®cant difference between the fed
and fasted conditions. Statistical signi®cance ofthe correlation between observed and calculated
values of plasma concentration were determinedby Pearson's method, which is a method to estimate the signi®cance for the linear correlation by
calculating Pearson's correlation coef®cient.

THEORETICAL SECTION
The GI transit±absorption model incorporatinga lagtime factor in ileocecal region is shown in
Figure 1. Although we de®ned it as eight segments

GAMMA SCINTIGRAPHIC EVALUATION OF GASTROINTESTINAL TRANSIT OF THEOPHYLLINE

467

Figure 1. The GI transit±absorption model is a pharmacokinetic model containing a
GI transit and an absorption process in each segment. Key: (D) initially administereddose; Xi  amount of drug in the segment i; ki  ®rst-order transit rate constant from thesegment i; kai  ®rst-order absorption rate constant for the segment i; Tlag  onset time totransit from the ileum to cecum; kel  ®rst-order elimination rate constant from centralcompartment; F bioavailability without ®rst-pass elimination.

in the previous studies,4,20 gastrointestinal tract
was divided into four segments because it wasdif®cult to distinguish the upper part from thelower of jejunum or ileum by gamma scintigraphic
images. An absorbable drug transits from asegment to the next segment with segmental
absorption (®rst-order absorption). Gastric emptying rate and transit rate for each segment
are represented by eqs. 1±4, by substituting zerofor kai in the case of a nonabsorbable drug like
[99mTc]DTPA, which corresponds to the GI transit±kinetic model.
dXs ÿ ks  kas   Xs
dt1

where at t  0, Xs  Dpo (the dose of the orally
administered drug).
dXjej
 ks  Xs ÿ kjej  kajej   Xjej
2
dt
dXile
 kjej  Xjej ÿ kaile  Xile0  t  Tlag dt kjej  Xjej ÿ kile  kaile   Xilet > Tlag 3dXce kile  Xile ÿ kco  kaco   Xco
dtt > Tlag 
4

where X, k, and ka represent the amount, thetransit rate constant, and the absorption rate
constant, respectively, Tlag represents an onset
time when the dug transits from the ileum tocecum in the ileocecal region, and the subscripts
for parameters indicate each GI site.
The prediction of the plasma concentration±
time curve by the convolution method consists offour-step analyses as described in our previous
paper.4 The predicted pro®le represents the plasma
concentration±time pro®le without the ®rst-passelimination in intestinal epithelium and/or liver.

RESULTS AND DISCUSSION
The technique of gamma scintigraphy was introduced for the evaluation of oral dosage forms morethan 20 years ago.7 Since then, the use of gamma
scintigraphy has been well established and utilized to assess GI transit in experimental and
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 90, NO. 4, APRIL 2001

468

HARUTA ET AL.

Figure 2. Typical scintigraphic images of orally administered [99mTc]DTPA along the
GI tract: (Scene 1) 7 min; (Scene 2) 153 min; (Scene 3) 295 min after oral administration.

clinical practice.8±16 In this study, we applied thistechnique to rats and examined the effect of GI
transit rate on the absorption kinetics of orally
administered aminophylline.
Figure 2 shows typical gamma scintigraphic
images of [99mTc]DTPA passing through the GI
tract postdose. Orally administered [99mTc]DTPA
was con®rmed to periodically migrate below along
the GI tract. It is dif®cult to discriminate jejunum
from ileum in the gamma scintigrapy images.
However, as Digenis et al. reported,13 it waspossible to subdivide the small intestine by closely
examining the relative position of the radioactivity within the ®eld of view of the gamma camera.
Figure 3 shows both observed time courses of therelative percent of radioactivity in each segment
determined by the gamma scintigraphic study andtheoretical curves based on the GI transit±kinetic
model in rats in each feeding condition. Because alagtime is clearly observed in the transit processfrom the ileum to the cecum in every study, thelagtime was introduced in the GI transit±kinetic
model. A similar lagtime was observed in a humanstudy.13 The necessity of a lagtime means that itis dif®cult to describe the transit kinetics in ileumby a single well-stirred compartment. However,as is evident from the ®gure, the theoretical curveof radioactivity for each segment, which was obtained from the ®tting analysis, was signi®cantly
in good agreement with the observed data ineach individual study. This result indicates that
the GI transit±absorption model, which consistsof four GI segments with a lagtime factor in theileocecal region, could be practically useful. The
corresponding GI transit parameters are summarized in Table 1. GI transit rate constants forstomach (ks) and jejunum (kjej) were reasonable
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 90, NO. 4, APRIL 2001

values by comparison with their corresponding
CLgi values4 (CLgi represents the transit clearance in the segment i, calculated model independently with the equation: CLgi  100/AUCRi0±12h,
where AUCRi0±12h indicates the area under thepercent of dosed total radioactivity versus time
curve from 0 to 12 h after dosing). However, in thecase of ileum, larger values of kile than CLgi ofileum were given in four of six cases because of
introducing a lagtime factor into the ileocecal
region, which means CLgi should be utilized to
discuss the intestinal transit of drug in thisstudy. Although the introduction of lagtime factor
to the GI transit±absorption model sometimes
resulted in overestimation of ki values, such afactor has been found to be quite useful for thedescription of the GI transit of drug after oral
administration.
GI transit behavior was remarkably affected by
the different food conditions. Under the fasted
condition, gastric emptying of [99mTc]DTPA wascompleted by 1 h postdose for all three rats
examined, resulting in gastric emptying clearance(CLgs) from 6.63 to 29.76 h ÿ 1. Therefore, almost
the entire dosed marker reached the cecum
within 4 h. In contrast, under the fed condition
CLgs signi®cantly decreased to 0.35 to 3.92 h ÿ 1(1.10  1.07 h ÿ 1, p < 0:05), and in two of threecases, the gastric emptying was not complete even
6 h postdose, resulting in the prolongation of thetime for all the marker dosed to reach the cecum.
On the other hand, the same tendency was found
for the transit in jejunum and ileum under bothfood conditions, as can be seen in the values of
CLgi. These results support the reports regarding
the effect of food on the GI transit of drugs inhuman;6,22±24 that is to say, the food would delay

GAMMA SCINTIGRAPHIC EVALUATION OF GASTROINTESTINAL TRANSIT OF THEOPHYLLINE
469

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 90, NO. 4, APRIL 2001

Figure 3. Time course of the remaining percent of dosed total radioactivity in each GI segment after oral administration of[99mTc]DTPA in rats. [99mTc]-DTPA solution was administered intragastrically. Experiments were performed for 3 rats (a, b, andc) under fasted and fed conditions. Scintigraphic images were taken at 2-min intervals for 6 h. Observed time courses of theremaining percent of dosed total radioactivity in each GI segment are expressed as follows: (*), stomach; (~), jejunum; (&),
ileum; (  ), cecum and below. Calculated time courses of the percent of dosed total radioactivity in each GI segment are expressedby solid lines, using ki values obtained from the ®tting by MULTI(FILT) program. Statistical signi®cance of the correlation
between observed and calculated values was examined by Pearson's method.

470

HARUTA ET AL.

Table 1.

Gastrointestinal Transit Parameters for Each Segment
GI Transit Rate Constant (hÿ1 =CLgi hÿ1 a

Food condition
FastedRat No.

StomachJejunum

Ileum

Cecumc and belowa

31:171=
29.76
6:89=
6.63
28:75=
25.91
22:27  13:37=
20:77  12:39

0:55=
0.57
1:19=
1.28
1:17=
1.23
0:97  0:36=
1:03  0:40

1:23=
0.30
1:71=
0.39
5:98=
0.45
2:97  2:61=
0:38  0:08

0:199=
Ðb
0:404=
Ðb
0:182=
Ðb
0:262  0:124=
Ðb

3:57=
3.92
0:34=
0.35
0:36=
0.39
1:42  1:86=
1:10  1:07d

0:60=
0.60
2:43=
2.24
0:59=
0.59
1:21  1:06=
1:74  0:97

1:10=
0.29
0:17=
0.27
0:27=
0.34
0:51  0:51=
0:34  0:24

0:056=
Ðb
0:372=
Ðb
0:043=
Ðb
0:157  0:186=ÐbbcMean  SD
Fed

a
b
c

Mean  SD

Lagtime (h)
3.79
2.83
2.54
3:05  0:65
4.22
2.93
4.17
3:18  1:80

The gastrointestinal transit rate constant for each segment and a lagtime in the ileocecal region were obtained from the ®tting of
the experimental data to GI transit±kinetic model by using MULTI (FILT) program.
aCLgi , the transit clearance in segment i, was calculated by 100/AUCR0±12 h, where AUCR0±12 h is the area under the percent ofdosed total radioactivity versus time curve for each segment calculated by the trapezoidal rule.
b
Not calculated.
c 10ÿ3 hÿ1 .
d
p < 0:05, compared with fasted condition.

the gastric emptying but not the intestinal transitof drugs.
Larger and the smaller values of CLgi instomach and jejunum, respectively, than thosein our previous report4,20 were noted. Somepossible explanations for this result are as follows:(1) different compartment models were employed;(2) rats were kept in the different types of therestraining cages; (3) different nonabsorbablemarkers were utilized; and (4) the parameters in
the previous report were obtained from theaveraged values, which include large interindividual variance, whereas in the present study, theparameter for each individual subject was used.
Although we need to ®gure out which factor wouldin¯uence predominantly GI transit of drug, itshould be taken into consideration that GI transit
might be changed easily by some factors, evenunder the fasted condition.
The plasma concentration±time curve of theophylline after oral administration of aminophylline was estimated for each rat using GI transit
rate constants determined for each rat in thefasted and fed conditions, according to our
prediction method.4 The results are shown in
Figure 4, together with the observed data. The
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 90, NO. 4, APRIL 2001

equation describing the plasma concentration oftheophylline after iv administration of aminophylline, which was used as the weight function,
is Cp  14:6eÿ26:2t  10:2eÿ0:31t . The predictedcurves were signi®cantly in good agreement withobserved data in all the individual studies. As
shown in Table 2, Tmax and Cpmax for theophylline,
which were well predicted by the GI transit±
absorption model, were remarkably in¯uenced by
the presence of food, although the difference inTmax was not signi®cant because of large interindividual variability. This effect on the plasma
concentration±time curve is caused by the alteration of GI transit behavior, mainly gastric emptying. In our previous study using rats with GI
transit rate retarded by propantheline,20 wereported that changes in the absorption pro®lescould re¯ect the retarded gastric emptying rate,
because theophylline is rapidly absorbed and theabsorbability is not so different among thesegments of the small intestine. The delay of gastric emptying by ingested foods was also reported
to cause the delay of the absorption of several
drugs, including theophylline in human,6,23 whichcoincided with our present result about therelationship among food, gastric emptying andGAMMA SCINTIGRAPHIC EVALUATION OF GASTROINTESTINAL TRANSIT OF THEOPHYLLINE

471

Figure 4. Plasma concentration±time curves of theophylline after oral administration of aminophylline in threerats (a, b, and c) under fasted and fed conditions. Aminophylline was administered at the dose of 5 mg/kg. Results are
expressed with an open circle for each experiment. Each predicted plasma concentration±time profile is expressed by
the solid line, using the individual GI transit data obtained by the fitting analysis. Statistical significance of thecorrelation between observed and calculated values was examined by Pearson's method.

Table 2. Comparison of Pharmacokinetic Parameters for Theophylline Predicted by GI Transit±Absorption Modelwith those from Observed Data
Observed=Predicteda
Food Condition
FastedMean  SD
Fed
Mean  SD

Tmax
(h)

Cpmax
(mg/mL)AUC(mg/mL  h)abc

0:25=0:20
0:50=0:50
0:08=0:22
0:28  0:21=
0:31  0:17

10:86=10:28
9:38=9:02
8:21=10:16
9:47  1:31=
9:82  0:70

28:13=29:36
28:72=28:30
26:44=29:23
27:76  1:18=
28:96  0:58abc

0:75=0:78
2:00=3:12
3:00=3:02
1:92  1:13=
2:31  1:32

7:91=8:28
3:44=4:02
3:73=4:16
5:03  2:50b
5:49  2:42b

30:69=28:00
15:45=19:40
17.30/20.04
21:15  8:32=
22:48  4:79

Rat No.

a
Predicted parameters were calculated from the data simulated by the convolution method based on the GI transit±absorption
model. Tmax and Cp max were de®ned as the time to reach the maximum plasma concentration and the maximum plasma
concentration, respectively.
b
p < 0:05, compared with fasted condition.

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 90, NO. 4, APRIL 2001

472

HARUTA ET AL.

Figure 5. Simulation of theophylline amount remaining in stomach and small
intestine after oral administration of aminophylline in each GI transit condition. Timecourses of theophylline remaining in stomach and small intestine, which were
simulated by the convolution method, are expressed by the solid and dotted lines,
respectively.

drug absorption. Figure 5 shows the theophylline±time pro®les in the stomach and intestine.
This result also indicates that the gastric emptying rate determines the absorption rate of theophylline. However, this relationship is not thecase when the value of the gastric emptying
rate constant is much larger than the intrinsic
absorption rate constant of theophylline, likecases a and c in Figure 5. In such a case, theapparent absorption rate constant of theophylline from the GI tract is dependent on not thegastric emptying rate but the intrinsic absorptionrate.
In conclusion, the assessment of GI transit for
an individual study by gamma scintigraphy andthe prediction of the absorption kinetics by the GI
transit±absorption model made it possible toinvestigate the relationship between the GI transit rate and oral drug absorption pro®le in detail.
It was suggested that information about the GI
transit for each individual is important to predictthe plasma concentration±time curves of orally
administered drugs, especially under the fed condition. The combination of gamma scintigraphy
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 90, NO. 4, APRIL 2001

and the GI transit±absorption model is a promising method to analyze the absorption kinetics andtherefore administer safer and more ef®cient
dosages in human.

REFERENCES
1. Davis SS, Hardy JG, Fara JW. 1986. Transit ofpharmaceutical dosage forms through the small
intestine. Gut 27:886±892.
2. Dressman JB, Berardi RR, Elta GH, Gray TM,
Montgomery PA, Lau HS, Pelekoudas KL, Szpunar
GJ, Wagner JG. 1992. Absorption of ¯urbiprofen in
the fed and fasted state. Pharm Res 9:901±907.
3. Snape WJ, Jr, Battle WM, Schwartz SS, Braunstein SN, Goldstein HA, Alavi A. 1982. Metoclopramide to treat gastroparesis due to diabetes mellitus:
A double-blind, controlled trial. Ann Intern Med
96:444±446.
4. Sawamoto T, Haruta S, Kurosaki Y, Higaki K,
Kimura T. 1997. Prediction of plasma concentration
pro®le of orally administered drugs on the basis ofgastrointestinal transit kinetics and absorbability
in rats. J Pharm Pharmacol 49:450±457.

GAMMA SCINTIGRAPHIC EVALUATION OF GASTROINTESTINAL TRANSIT OF THEOPHYLLINE

5. Kutcahi HC. 1998. The gastrointestinal system. In:
Berne RM, Levy MN, editors. Physiology, 4th ed.
St. Louis: Mosby, p. 589±674.
6. Hebbard GS, Sun WM, Bochner F, Horowitz M.
1995. Pharmacokinetic considerations in gastrointestinal motor disorders. Clin Pharmacokinet 28:
41±66.
7. Casey DL, Beihn RM, Digenis GA, Shabhu MB.
1976. Method for monitoring hard gelatin capsuledisintegration times in humans using external
scintigraphy. J Pharm Sci 65:1412±1413.
8. Theodorakis MC, Digenis GA, Beihn RM, Shambhu
MB, Deland FH. 1980. Rate and pattern of gastric
emptying in human using 99mTc-labeled triethylenetetraamine-polystyrene resin. J Pharm Sci 69:
568±571.
9. Digenis GA, Sandefer E. 1991. Gamma scintigraphy and neutron activation techniques in the in vivo
assessment of orally administered dosage forms.
Crit Rev Ther Drug Carrier Syst 7:309±345.
10. Harris D, Fell JT, Sharma HL, Taylor DC. 1990. GI
transit of potential bioadhesive formulations in
man: A scintigraphic study. J Controlled Release
12:45±53.
11. Christian PE, Moore JG, Sorenson JA, Coleman
RE. Welch DM. 1980. Effects of meal size and correction technique on gastric emptying time: Studies
with two tracers and opposed detectors. J Nucl Med
9:883±885.
12. Wilding IR, Coupe AJ, Davis SS. 1991. The role ofgamma scintigraphy in oral drug delivery. Adv
Drug Deliv Revs 7:87±117.
13. Digenis GA, Sandefer EP, Page RC, Doll WJ. 1998.
Gamma scintigrapy: An evolving technology inpharmaceutical formulation developmentÐPart 1.
Pharm Sci Technol Today 1:100±107.
14. Digenis GA, Sandefer EP, Page RC, Doll WJ. 1998.
Gamma scintigrapy: An evolving technology inpharmaceutical formulation developmentÐPart 2.
Pharm Sci Technol Today 1:160±165.

473

15. Palin KJ, Whalley DR, Wilson CG, Davis SS,
Phillips AJ. 1982. Determination of gastric-emptying pro®les in the rat: In¯uence of oil structure andvolume. Int J Pharm 12:315±322.
16. Goggin JM, Hoskinson JJ, Butine MD, Foster LA,
Myers NC. 1998. Scintigraphic assessment of gastric emptying of canned and dry diets in healthycats. Am J Ver Res 59:388±392.
17. Ogiso T, Iwaki M, Tanino T, Okuyama K, Uno S.
1993. Effect of mexiletine on elimination andmetabolic conversion of theophylline and its major
metabolites in rats. Biol Pharm Bull 16:163±167.
18. Yano Y, Yamaoka K, Tanaka H. 1988. A nonlinear
least squares program, MULTI (FILT), based on
fast inverse laplase transform for microcomputer.
Chem Pharm Bull 37:1035±1038.
19. Kakemi K, Sezaki H, Konishi R, Kimura T, Okita A.
1970. Effect of bile salts on the gastrointestinal
absorption of drugs.II. Mechanism of the enhancement of the intestinal absorption of sulfaguanidine
by bile salts. Chem Pharm Bull 18:1034±1039.
20. Haruta S, Iwasaki N, Ogawara K, Higaki K,
Kimura T. 1998. Absorption behavior of orally
administered drugs in rats treated with propantheline. J Pharm Sci 87:1081±1085.
21. Shiu GK, Sager AO, Velagapudi RB, Prasad VK,
Skelly JP. 1988. The effect of food on the absorptionof controlled-release theophylline in mini-swine.
Pharm Res 5:48±52.
22. Davis SS, Hardy JG, Fara JW. 1986. Transit ofpharmaceutical dosage forms through the small
intestine. Gut 27:886±892.
23. Peh KK, Yuen KH. 1996. Indirect gastrointestinlatransit monitoring and absorption of theophylline.
Int J Pharm 139:95±103.
24. Abrahamsson B, Alpsten M, Hugosson M, Jonsson
UE, Sundgren M, Svenheden A, Tolli J. 1993.
Absorption, gastrointestinal transit, and tablet
erosion of felodipine extended-release (ER) tablets.
Pharm Res 10:709±714.

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 90, NO. 4, APRIL 2001