International Journal of Pharmaceutics 233 (2002) 179– 190
www.elsevier.com/locate/ijpharmPrediction of plasma concentration –time curve of orally
administered theophylline based on a scintigraphic
monitoring of gastrointestinal transit in human volunteers
Shunji Haruta a,d, Keiichi Kawai b, Ryuichi Nishii c, Seishi Jinnouchi c,
Ken-ichi Ogawara d, Kazutaka Higaki d, Shozo Tamura c, Kazuhiko Arimori a,
Toshikiro Kimura d,*a

Department of Hospital Pharmacy, Miyazaki Medical College, Miyazaki 889 -1692, Japanb
Central Research Laboratories, Miyazaki Medical College, Miyazaki 889 -1692, Japanc
Department of Radiology, Miyazaki Medical College, Miyazaki 889 -1692, Japand
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama Uni6ersity, Okayama 700 -8530, Japan
Received 23 August 2001; received in revised form 24 October 2001; accepted 30 October 2001

Abstract
The plasma concentration–time profile of theophylline after oral administration in human volunteers was predictedusing the individual gastrointestinal (GI) transit data monitored by a gamma scintigraphic technique. Theophylline
was administered as aminophylline under fasted and fed condition, along with 99mTc-labeled diethylenetriamine-pentaacetic acid (DTPA), an unabsorbable marker to evaluate the GI transit by a gamma scintigraphic technique. Twohealthy male volunteers participated under fasted and fed conditions in a crossover study. The GI transit wasevaluated by dividing the GI tract to four segments, stomach, jejunum, ileum and cecum/colon. Under the fed
condition, the GI transit pattern for each segment was confirmed to alter considerably, causing a delay in the gastric
emptying mainly. Further, the plasma concentration curves of theophylline after oral administration were predictedusing the GI-Transit-Absorption Model on the basis of individual GI transit parameters calculated by the fitting of
the observed data to the GI-Transit Kinetic Model. The absorption rate constant in each segment and thepharmacokinetic parameters after intravenous administration used for the prediction were the values extrapolated
from the data in rats and the ones normalized from the values in literatures, respectively. The plasma concentration–
time curves for theophylline were well predicted using obtained individual GI transit parameters. The analysis using
this method could estimate the variable absorption behavior governed by the GI transit in detail. © 2002 Elsevier
Science B.V. All rights reserved.
Keywords: Oral absorption; Gastrointestinal transit; Gamma scintigraphy; Human; GI-transit-absorption model; Prediction ofabsorption profile* Corresponding author. Tel.: + 81-86-251-7948; fax: + 81-86-251-7926.
E-mail address: kimura@pheasant.pharm.okayama-u.ac.jp (T. Kimura).
0378-5173/02/$ - see front matter © 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 3 7 8 - 5 1 7 3 ( 0 1 ) 0 0 9 4 2 - 5

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S. Haruta et al. / International Journal of Pharmaceutics 233 (2002) 179–190

1. Introduction
The rate and extent of oral drug absorption
from the GI tract are governed by two major
factors, the permeability of gastrointestinal (GI)mucosa and the GI transit rate. Pharmacokinetic
analysis for the plasma concentration– time curveof an orally administered drug is generally performed using a first-order absorption model fromthe whole GI tract, regarded as a single compartment. Since there are site-differences in the absorbability of drugs and the residence time
(Stripp, 1965; Rebecca and Amidon, 1987; Gramatte, 1994) it is hard to analyze the absorption
process from the GI tract in detail using such asimple model. Furthermore, the GI transit rate ischangeable by various factors, e.g. individual differences (Davis et al., 1986), meals (Dressman etal., 1992), disease states (Snape et al., 1982) andso on, resulting in the remarkable alteration ofabsorption behavior of orally administered drugs.
In our previous papers (Sawamoto et al., 1997;
Haruta et al., 1998), a novel method based on the
GI transit kinetics was developed for estimating
the absorption profiles of drugs administeredorally as an aqueous solution. In those cases, theGI transit was evaluated as averaged values using
phenol red as an unabsorbable marker. The validity and the utility of the prediction method havebeen demonstrated for model drugs with different
absorption characteristics in rats. Furthermore, toevaluate the drug absorption process regulated by
the GI transit more precisely, the prediction of theplasma concentration– time curve after oral administration was performed with each individualtransit data using a gamma scintigraphy and it
became possible to estimate the variable absorption behavior governed by the GI transit in detailin rats (Haruta et al., 2001).
In the present study, our prediction method forplasma concentration–time curve of orally administered drugs was applied to two healthy volunteers on the basis of the GI transit monitoring
using a gamma scintigraphy, a non-invasive technique, under fasted and fed conditions in the
crossover study. The use of gamma scintigraphy
to monitor the GI transit in the experimental andclinical practice has been well established andutilized (Casey et al., 1976; Theodorakis et al.,
1980; Harris et al., 1990; Digenis and Sandefer,
1991). This technique leads to evaluate GI transit
and oral absorbability simultaneously in the same
individual. As an absorbable drug without firstpass metabolism after oral administration (Ogiso
et al., 1993), aminophylline was administeredalong with 99mTc-labeled diethylenetriamine-pentaacetic acid (99mTc-DTPA), an unabsorbablemarker. The prediction of plasma concentration–
time curves of theophylline in each individual was
performed. In addition, the effect of the food on
the absorption behavior was also investigated.

2. Materials and methods

2.1. Materials
Aminophylline (Neophylline® injection) was
supplied by Eisai Ltd (Tokyo, Japan) andtheophylline (Tokyo Kasei Kogyo Co, Tokyo,
Japan) was obtained commercially. All otherchemicals and reagents were analytical grade commercial products. 99mTc was obtained as sodium
pertechnetate solution by elution of a generator,
and 99mTc-DTPA was prepared using a kit containing calcium trisodium diethylenetriamine-pentaacetate and stannous chloride dihydrate(Daiichi Radioisotope Lab, Tokyo, Japan).

2.2. Volunteers
Two healthy male volunteers, non-smokers,
aged 27 and 29 years participated in the study
with written informed consent, which was approved by our local ethical committee atMiyazaki Medical College.

2.3. In 6i6o study design
The study was performed for each subject under two different food conditions at an interval ofa month. Under the fasted condition, each subject
was dosed after a 12-h overnight fast. While,
under the fed condition, each subject was dosed 1
h after a light breakfast consisting of a slice ofbread, a scramble egg, two boiled sausages and a

S. Haruta et al. / International Journal of Pharmaceutics 233 (2002) 179–190

glass of orange juice. Food was withheld for atleast 5 h after the drug administration. Undereach food condition, aminophylline (100 mg) was
administered as the 30 ml of aqueous solution
containing 99mTc-DTPA (4 – 5 mCi), followed by
70 ml of water. After the drug dosing, imaging
was immediately undertaken with a subject on hisback using a gamma camera (PRISM 2000, Picker
Int, Cleveland, OH). Blood samples of 5 ml weredrawn after 15, 30, 45, 60, 90, 120, 180, 240, 360
and 480 min through an intravenous catheter, andthe serum was obtained for the determination oftheophylline concentration.

gion, using a non-linear regression program,
MULTI (FILT) (Yano et al., 1988).

2.6. Estimation of absorption parameters for eachsegment in human
The absorption rate constant of theophylline
for each GI segment in human, which is necessary
for the prediction of the plasma concentration–
time curve after oral administration, was estimated using absorption data of theophylline inrats according to Eq. (1), introduced by Yuasa(1998).
kahuman = 0.744·karat

2.4. Gamma scintigraphic imaging
Gamma scintigraphy, a non-invasive technique,
was employed to measure the GI transit rate foreach segment. An aqueous solution of 99mTcDTPA, an unabsorbable compound, was prepared as a tracer passing through the GI tract.
The gamma scintigraphic imaging was carried out
for 480 min. For the first 60 min, imaging wascontinuously carried out at 2-min intervals under
the dynamic planar condition, beginning immediately after dosing, and then imaging was carriedout for 2 min each after 90, 120, 150, 180, 240,
300, 360, 420 and 480 min under the static planar
condition. During the non-imaging time, subjects
were allowed free action.

2.5. Determination of GI transit rate constant foreach segment
GI tract was divided into four segments, i.e.
stomach (s), jejunum (jej), ileum (ile) and cecum/colon (co). The radioactivity in each segment wasthen measured from each region of interest (ROI)
using a mini super computer (ODDYSEY, Picker
Int, Cleveland, OH), and the relative percent ofradioactivity for each ROI versus time was generated. The GI transit rate constant (ki) for eachsegment in the individual study was obtained
from the fitting of the experimental GI transit
data to the modified GI-Transit Kinetic Model(Haruta et al., 2001), a linear transit kinetic model
incorporating a lag time factor in ileo– cecal re-

181

(1)

where kahuman and karat represent the absorption
rate constants in human and rats, respectively.

2.7. Pharmacokinetic parameters of theophylline
after intra6enous administration
Pharmacokinetic parameters for theophylline
after intravenous bolus administration in human,
which are used as a weight function for the convolution in the prediction method, were calculated from the data of 24 human subjects
reported by Mitenko and Ogilvie (1972, 1973,1974). They are not only normal volunteers but
also asthmatic subjects. But the authors showedthat the pharmacokinetic parameters in thegroup of asthmatic subjects were not significantly different from those in the group of normal volunteers (Mitenko and Ogilvie, 1974),
where the plasma concentration profiles were analyzed by a two-compartment model and wereexpressed as Cp=A exp(−ht)+ B exp(− it).
The parameters were normalized to the values atthe dose of 1 mg/kg. The results are summarizedin Table 1.

2.8. Analytical method
Blood samples were collected in heparinizedtubes. Theophylline in the plasma was assayed by
a fluorescence polarization immunoassay method,using an Abbott TDx (Abbott Lab, Chicago, IL).
The coefficient of variation (CV) of the standard
curve ranged from 3.09 to 3.21% and the squared
correlation coefficient was over 0.997.

S. Haruta et al. / International Journal of Pharmaceutics 233 (2002) 179–190

182

Table 1
Normalized pharmacokinetic parameters for theophylline after intravenous administration in human
Subject

Age, sex

Disease

Dose (mg/kg)

Parameters at the dose of 1 mg/kg

Reference

A (mg/ml)

B (mg/ml)h (per h)i (per h)

C.A.

22, M

Normal

2.4

1.173

2.095

3.948

0.162

W.W.

31, M

Normal

2.4

0.066

2.075

1.489

0.139

P.R.

25, M

Normal

2.4

0.264

1.708

10.572

0.138

M.R.

21, M

Normal

2.4

0.602

1.318

0.249

0.098

C.S.

25, M

Normal

2.4

3.698

2.082

9.116

0.104

C.W.a

24, M

Normal

2.4

2.560

1.904

6.186

0.242

R.L.

30, M

Normal

2.4

5.543

2.521

9.942

0.194

F.S.

22, M

Normal

2.4

5.296

2.111

5.423

0.177

M.W.

19, M

Normal

2.4

0.118

2.339

4.108

0.166

H.W.

34, M

Asthmatic

5.6

0.282

1.873

5.152

0.130

V.W.b

53, F

Asthmatic

5.6

0.131

2.845

2.595

0.114

A.G.

37, M

Asthmatic

5.6

2.414

2.030

4.744

0.171

A.E.

43, F

Asthmatic

5.6

2.282

2.435

5.727

0.141

V.M.

47, F

Asthmatic

5.6

5.807

2.597

13.519

0.241

J.L.

43, M

Asthmatic

5.6

0.191

2.266

2.170

0.168

T.S.

51, F

Asthmatic

5.6

3.134

2.548

8.017

0.166

C.S.

25, M

Normal

2.4

2.744

2.358

5.830

0.099

R.L.

30, M

Normal

2.4

5.801

2.463

8.350

0.190

F.S.

22, M

Normal

2.4

5.569

2.183

4.890

0.183

1

21, M

Normal

4

0.017

2.446

1.697

0.131

2

22, M

Normal

4

1.176

2.214

2.212

0.131

3

18, M

Normal

4

0.589

1.988

1.379

0.084

4

21, M

Normal

4

1.555

1.941

5.462

0.129

5

19, M

Normal

4

0.549

2.349

2.063

0.098

2.148
2.100

2.196
0.327

5.202
3.352

0.150
0.042

Mean
S.D.

Plasma concentration–time profiles were expressed as Cp = A exp(−ht)+B exp(−it).
aSubject showing the highest plasma profile.
b
Subject showing the lowest plasma profile.

Mitenko andOgilvie, 1973
Mitenko andOgilvie, 1973
Mitenko andOgilvie, 1973
Mitenko andOgilvie, 1973
Mitenko andOgilvie, 1973
Mitenko andOgilvie, 1973
Mitenko andOgilvie, 1973
Mitenko andOgilvie, 1973
Mitenko andOgilvie, 1973
Mitenko andOgilvie, 1973
Mitenko andOgilvie, 1973
Mitenko andOgilvie, 1973
Mitenko andOgilvie, 1973
Mitenko andOgilvie, 1973
Mitenko andOgilvie, 1973
Mitenko andOgilvie, 1973
Mitenko andOgilvie, 1972
Mitenko andOgilvie, 1972
Mitenko andOgilvie, 1972
Mitenko andOgilvie, 1974
Mitenko andOgilvie, 1974
Mitenko andOgilvie, 1974
Mitenko andOgilvie, 1974
Mitenko andOgilvie, 1974

S. Haruta et al. / International Journal of Pharmaceutics 233 (2002) 179–190

183

method, which is the one to estimate the significance for the linear correlation by calculating
Pearson’s correlation coefficient.

3. Theoretical

3.1. GI-Transit-Absorption Model

Fig. 1. GI-Transit-Absorption Model. GI-Transit-Absorption
Model is a pharmacokinetic model containing a GI transit andan absorption process in each segment. D, initially administered dose; Xi, amount of drug in the segment i; ki, first-ordertransit rate constant from the segment i; kai, first-order absorption rate constant for the segment i; Tlag, onset time totransit from the ileum to cecum; kel, first-order elimination
rate constant from central compartment; F, bioavailability
without first-pass metabolism.

GI-Transit-Absorption Model, a model thatcan predict in vivo absorption kinetics containing
GI transit and absorption of drugs administeredorally, is shown in Fig. 1. The whole GI tract isdivided into four segments (stomach, jejunum,
ileum and cecum/colon), and the drug dispositionin each segment is defined as the well-stirredcondition. An absorbable drug transits from asegment to the next segment with segmental absorption (first-order absorption). Gastric emptying rate and transit rate for each segment are
represented by Eqs. (2)–(5), respectively. Theseequations can describe the GI transit of an unabsorbable drug, such as 99mTc-DTPA, when kai isdefined as zero, corresponding to GI-Transit Kinetic Model.
For stomach:dXs= − (ks + kas)Xs
dt(2)

where at t=0, Xs = Dpo (the dose of the orally
administered drug).
For jejunum:dXjej= ksXs − (kjej + kajej)Xjej
dt(3)

For ileum:Fig. 2. Scintigraphic image of human GI tract and ROI ofeach GI segment. Scintigraphic image of whole GI tract was
obtained by piling up each image of GI tract after oral
administration of 99mTc-DTPA solution.

dXile= kjejXjej − kaileXiledt(05t5 Tlag)dXile= kjejXjej − (kile + kaile)Xile
dt(t]Tlag)(4)

2.9. Statistical analysis
Statistical significance of the correlation between observed and calculated values of plasma
concentration was determined by Pearson’s

For cecum/colon:
dXco= kileXile − (kco + kaco)Xco
dt(t]Tlag)(5)

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S. Haruta et al. / International Journal of Pharmaceutics 233 (2002) 179–190

where X, k and ka represent the amount, thetransit rate constant and the absorption rate constant, respectively. Tlag, representing an onset time
when the drug begins to transit from the ileum tocecum in the ileo-cecal region, was introduced todescribe more precisely the characteristic motility
in ileo–cecal region.

formation of the obtained equation by the convolution program (Yamaoka and Tanigawara, 1984)
gives the predicted plasma concentration profile
after oral administration without the first-passmetabolism in intestinal epithelium and/or liver.

4. Results and discussion

3.2. Prediction method
The prediction method using convolution analysis consists of four processes (Sawamoto et al.,1997). In step 1, the drug amount– time profile ineach segment is calculated by the convolution
method. In step 2, the absorption rate– time
profile in each segment is calculated by using the
drug amount – time profile in each segment, calculated in step 1. In step 3, the absorption rate– time
profile in the whole GI tract is calculated as thesum of the absorption rate– time profiles of four
segments obtained in step 2. In step 4, predictionof the plasma concentration– time curve of orally
administered drug is performed by means of the
convolution method. The total absorption rate–
time data obtained in step 3 and pharmacokinetic
parameters after intravenous administration correspond to the input function and the weightfunction, respectively. The inverse Laplace trans-

The use of a gamma scintigraphy for the evaluation of GI transit has been well established andutilized in clinical practice (Casey et al., 1976;
Theodorakis et al., 1980; Harris et al., 1990; Digenis and Sandefer, 1991). Thus, it is not difficult
to introduce a gamma scintigraphic monitoring of
the GI transit to our prediction method for theplasma concentration–time curve of orally administered drug in the human study. In thepresent study, we attempted to examine the effectof GI transit rate on the absorption kinetics oforally administered aminophylline.
Fig. 2 shows the scintigraphic image of thewhole GI tract, obtained by piling up each imageof the GI tract acquired after oral administrationof 99mTc-DTPA, and each ROI located for four
divided GI segments. The location of ROI for
each segment was performed by referring to theprevious report (Digenis et al., 1998). ROIs forFig. 3. Comparison of typical scintigraphic images of human GI tract after oral administration of 99mTc-DTPA solution under eachfood condition. Scintigraphic images of GI tract of Subject S.H. under both food conditions after oral administration of99m
Tc-DTPA solution was picked up periodically. ROIs are shown by dotted lines.

S. Haruta et al. / International Journal of Pharmaceutics 233 (2002) 179–190

185

Fig. 4. Observed and calculated time courses of the remaining percent of dosed total radioactivity for each GI segment after oral
administration of 99mTc-DTPA solution in human volunteers. Observed time courses of the remaining percent of dosed total
radioactivity in each GI segment are expressed as follows: (2) stomach; () jejunum; ( ) ileum; (+ ) cecum/colon. Calculated timecourses of the percent of dosed total radioactivity in each GI segment are expressed by solid lines by using ki values obtained fromthe fitting by MULTI (FILT) program.

the stomach and cecum/colon were readily identified by their characteristic anatomical shapes,
respectively. On the other hand, ROIs for the
jejunum and ileum were located by drawing a
vertical or diagonal midline that approximately
bisects the field of the whole small intestine since
the line of demarcation for the small intestine is
not clear.
To compare the difference in GI transit behavior between both food conditions, typical scintigraphic images of GI tract under both foodconditions were monitored periodically (Fig. 3).
As is evident from the figure, the GI transit
pattern considerably altered by the food condition. At 2-min post dose, almost the entire dosed
radioactive marker existed in the stomach underboth food conditions, and the relative size of ascintigraphic image of the stomach under the fed
condition indicated the characteristic gastricshape after meals. At 30 min post dose, almost allof the radioactive marker dosed under the fasted
condition was emptied from the stomach andexisted in the small intestine, mainly ileum, while
the marker dosed under the fed condition still
remained in the stomach. After 240 min, theentire radioactive marker dosed under the fasted
condition already reached to the cecum andcolon, while the marker dosed under the fasted
condition still existed in the small intestine,
mainly ileum. At 480 min post dose, almost theentire dosed radioactive marker has reached tothe colon (mainly ascending colon) under bothfood conditions. Particularly, the radioactive
marker dosed under the fed condition was slightly

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S. Haruta et al. / International Journal of Pharmaceutics 233 (2002) 179–190

observed in the transverse colon, suggesting thatthe intestinal motility below the cecum under the
fed condition might be rather higher than that
under the fasted condition.
Fig. 4 shows both the observed time courses of
the relative percent of radioactivity in each GI
segment determined by the gamma scintigraphic
study and the theoretical curves based on themodified GI-Transit Kinetic Model with a lagtime factor in the ileo-cecal region. It is reasonable to put a lag time in the ileo-cecal region,
since there is a valve, which would contribute to
gut homeostasis by optimizing retention of chymein the small intestine until digestion is complete(Wilding, 2000). As is evident from the figure, thetheoretical curve of radioactivity for each GI segment, which was obtained from the fitting analysis, was in good agreement with the observed datain all the individual studies (0.9575 r5 0.977,
PB 0.001). The corresponding GI transit parameters are summarized in Table 2, but GI transit
rate constants thus calculated have been found to
be quite useful for the description of the GI
transit of a drug after oral administration. However, the transit rate constants thus calculated
merely for the ileum do not reflect the actual
transit of drugs, because of introducing a lag time

factor to the ileo– cecal region (Haruta et al.,2001). The GI transit clearance (CLgi), therefore,
was employed to discuss the GI transit. CLgi
represents the transit clearance in the segment i
calculated model-independently with the equation: CLgi = 100/AUCR (Sawamoto et al., 1997;
Haruta et al., 1998, 2001), where AUCR indicatesthe area under the percent of dosed total radioactivity versus time curve, and the values are also
summarized in Table 2. Under the fasted condition, the gastric emptying of the radioactive
marker in both subjects completed by 1-h postdose, resulting in the gastric emptying clearancesof 4.619 and 4.237 per h. And once the radioactive marker began to enter the cecum at approximately 3-h post dose, the cecum and colon werevery rapidly filled with the entire radioactive
marker until 5–7 h post dose. Similar profiles
were reported by Digenis et al. (1998) and they
indicated that the ileo-cecal valve regulated thetransit from the ileum to the colon and that thetime to reach the colon was around 3–5 h. On theother hand, under the fed condition, gastric emptying clearances decreased to 1.171 and 0.815 perh for each subject, resulting in the prolongation of
the time for all of radioactive marker dosed toreach the cecum and colon. There is, however, no

Table 2
Gastrointestinal transit parameter for each segment
Subject

Food condition

S.H.

Fastedki (per h)CLgi (per h)Fedki (per h)CLgi (per h)
Fastedki (per h)CLgi (per h)Fedki (per h)CLgi (per h)R.N.

StomachJejunum

Ileum

Cecum and below

Tlag (h)

4.853
4.619

0.721
0.729

2.429
0.297

–a
–

4.485
–

1.174
1.171

2.451
2.467

1.040
0.209

–a
–

5.121
–

4.413
4.237

4.156
4.331

3.085
0.334

–a
–

3.138
–

0.815
0.815

1.862
1.873

1.357
0.291

–a
–

4.411
–

The GI transit rate constant for each segment and a lag time in the ileo-cecal region were obtained from the fitting of theexperimental data to GI-Transit Kinetic Model by using MULTI (FILT) program (Yano et al., 1988). CLgi, the transit clearance
in segment i, was calculated by 100/AUCR (Haruta et al., 2001). AUCR means the area under the percent of dosed total
radioactivity versus time curve for each segment calculated by the trapezoidal rule.
a
Not calculated.

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187

Fig. 5. Plasma concentration profiles of theophylline after oral administration of aminophylline in human volunteers. Theophylline
was administered at the dose of 85 mg (100 mg)/body as aminophylline. Prediction of plasma concentration profile of theophylline
after oral administration of aminophylline, which is shown by solid line, was performed using three different sets of weight functions,i.e. (a) pharmacokinetic parameters obtained from a subject with the lowest plasma profile, (b) pharmacokinetic parameters averaged
from data of 24 subjects and (c) pharmacokinetic parameters obtained from a subject with the highest plasma profile after
intravenous administration of theophylline.

apparent effect of food on the transit parameters
for the jejunum and ileum. This observation is
supported with other report, where the food intake and dosed formulation delay the gastric emptying rate but not affect the small-intestinal
transit rate (Davis et al., 1986). Davis et al. (1986)
also reported that the rapid gastric emptying wasoften observed in a fasted state, but even a lightmeal delayed emptying, where the transit time
ranged from 10 to 100 min. These values arecomparable with our data, 13– 14 min in thefasted state and 50–74 min in the fed state. This isalso the case for the small-intestinal transit. Basedon the ki value for the ileum, the transit times are
between 180 and 202 min in the fasted state andare between 206 and 288 min in the fed state,comparing with 240–300 min by Davis et al.
(1986). The values of GE50% and SITT50%, thetimes to empty 50% of gastric contents and ofintestinal contents, respectively, presented by
Wilding (2000), also gave similar values in the rate
constant with our results (Table 2).
To predict the plasma concentration–timecurve after oral administration, the absorption
rate constant of theophylline for each GI segmentin human is needed. Although, in the rat study,
absorption rate constants of theophylline wereobtained by performing a conventional in situ
closed loop method for each GI segment(Sawamoto et al., 1997; Haruta et al., 1998, 2001),

S. Haruta et al. / International Journal of Pharmaceutics 233 (2002) 179–190

188

it is hard to estimate directly the corresponding
absorption parameter for each GI segment in
human. Therefore, the absorption rate constants
in human were calculated using the absorption
rate constants of theophylline obtained in rats
(Sawamoto et al., 1997) according to the relationship between kahuman and karat reported by Yuasa(1998), as described in the Methods section. The
equation, kahuman =0.744 karat, was introduced
from the difference in the surface area and luminal volume of the small intestine between humanand rats, based on the relationship of the permeability between human and rat reported by Amidon et al. (1988). The absorption rate constants
obtained for human GI segments are as follows;
stomach (unabsorbable), jejunum (8.84 per h) andileum (6.01 per h). Then, the plasma concentration –time curve of theophylline after oral administration of aminophylline was estimated for eachstudy using the ka values for human and individual GI transit rate constants in the fasted and fed
conditions, according to our prediction method.
The predicted plasma concentration– time curves
Table 3
Pharmacokinetic parameters of theophylline after oral administration of aminophylline in two human volunteers
Subject

S.H.

R.N.

Food condition

FastedPredicted
Observed
Fed
Predicted
Observed
FastedPredicted
Observed
Fed
Predicted
Observed

AUC (mg h/ml)
Lowa

Meanb

Highc

9.23

13.65
13.40

19.13

8.92

12.99
15.11

18.03

8.95

14.55
14.58

20.38

9.23

13.33
14.72

18.41

Predicted AUCs were calculated from the data simulated by
the convolution method based on the GI-Transit-Absorption
Model. The prediction was performed using three different sets
of weight function, i.e., pharmacokinetic parameters with thelowest plasma levela, the ones averaged from the data of 24
subjectsb and the ones with the highest plasma levelc (Table 1)
after intravenous administration of theophylline. The parameters were normalized at the dose of 1 mg/kg.

of theophylline are shown in Fig. 5, together withthe observed data and calculated pharmacokinetic
parameters are summarized in Table 3. The disposition parameters of theophylline after intravenous administration in human, which were used
as a weight function in the convolution analysis,
were data of 24 subjects cited from literatures(Mitenko and Ogilvie, 1972, 1973, 1974) (Table
1). Considering the interindividual variation of
the disposition parameters, the prediction was
performed using three different sets of weightfunctions, i.e. pharmacokinetic parameters averaged for 24 subjects (Cp= 2.15e − 5.20t +2.20e − 0.15t), the ones for the highest plasma
profile (Cp= 2.56e − 6.19t + 1.90e − 0.24t) and theones for the lowest plasma profile (Cp=
0.13e − 2.60t + 2.85e − 0.11t), which are normalized at
the dose of 1 mg/kg. The plasma concentration–
time curves predicted using the averaged parameters as the weight function are in good agreementwith the observed data in all the individual studies(0.7255 r5 0.960, PB0.05). Lower Cpmax andlarger Tmax in the plasma concentration–timecurves under the fed condition were observed thanunder the fasted condition (Fig. 5). This effect offood conditions on the plasma concentration–
time curve is caused by the alteration of the GI
transit behavior, mainly gastric emptying. Fig. 6
shows the amount of theophylline versus time
profiles in the stomach and small intestine, whichwere simulated using ki and kai values obtained in
the present study. Three cases except for S.H.
under fasted condition indicate that the gastric
emptying rate determines the absorption rate oftheophylline, in which a greater value of ks results
in a greater absorption rate of theophylline.
On the other hand, AUC values under bothfood conditions were almost same (Table 3), but
this is reasonable. As reported previously (Haruta
et al., 1998), AUC, an extent of bioavailability, is
not affected by the delay of the GI transit in thecase of a well-absorbable drug like astheophylline, because it is almost completely absorbed even under the condition where GI transit
is fast such as the fasted condition.
The GI transit parameters in each subject canbe estimated without accompanying affliction us-

S. Haruta et al. / International Journal of Pharmaceutics 233 (2002) 179–190

189

Fig. 6. Simulation of theophylline amount remaining in stomach and small intestine after oral administration of aminophylline ineach GI transit condition. Time courses of theophylline remaining in the stomach (a) and small intestine (b), which were simulatedby the convolution method, are expressed by solid lines, respectively.

ing a gamma scintigraphic technique. Using thesegmental absorption data in rats, which can beeasily obtained experimentally or from literatures,and the pharmacokinetic parameters after intravenous administration in human, which can beobtained through literature reference, the plasma
concentration profile for the concerned drug inthe individual would be predicted with the corresponding GI transit condition.
In the present study, we showed only two volunteers’ data, because it has been being very
difficult to perform human study, especially for abasic research in Japan. Therefore, we cannot
mention the conclusion from the viewpoint ofstatistics. However, the present results suggestthat our method using the GI-Transit-Absorption
Model and gamma scintigraphic technique is a
useful tool to analyze the drug absorption behavior and the effect of GI transit on it in human.

This method could offer the beneficial information for the drug development and to perform thesafer and more sufficient dosage regimen for theindividual patient in the clinical practice.

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