Journal of Pharmacokinetics and Biopharmaceutics, Vol. 4, No. 3, 1976

Kinetics of Indomethacin Absorption, Elimination, and Enterohepatic Circulation in Man K. C. Kwan, t G. O. Breault, 1 E. R. Umbenhauer, ~ F. G. McMahon, 2 and D. E. Duggan 1 Received Sept. 12, 1975--Final Dec. 8, 1975

There are no discernible quantitative differences in the biotransformation and the excretion of indomethacin following oral, rectal, and intravenous administration of indomethacin-l gc. Approximately 50 ~ (range 24-115 ~ f o r n = 6) of an intravenous dose undergoes enterohepatic circulation. Thus the bioavailability of indomethacin to the systemic circulation may exceed the administered dose. Relative to the intravenous dose, indomethacin is 80 and 100 % bioavailable from suppositories and capsules, respectively. Absorption and/or reabsorption appears to be more rapid and uniform by the rectal route. Recognition of the attributes of biliary recycling also helps to explain the observed variability in apparent plasma half-life, while their neglect requires alternative explanations for anomalies between the disappearance rate from plasma and the corresponding appearance rate in urine. KEY WORDS: biliary recycling; bioavailability; biotransformation; clearance; route dependence; enterohepatic circulation; indomethacin.

INTRODUCTION

The metabolic disposition of indomethacin following oral and intravenous dosages in man was described in a previous communication (1). Unchanged indomethacin (I), N-deschlorobenzoylindomethacin (DBI), Odesmethylindomethacin (DMI), and O-desmethyl-N-deschlorobenzoylindomethacin (DMBI) and their respective glucuronides accounted for all of the radioactivity in plasma, urine, and feces. The observed temporal relationship among all chemical species appeared to be adequately described by a minimal kinetic model composed of four separate mammillary subunits joined in a manner dictated by observed biotransformations. In addition, it was 1Merck, Sharp and Dohme Research Laboratories, West Point, Pennsylvania 19486. 2Tulane Therapeutics Section, Department of Medicine, New Orleans, Louisiana 70112. 255 0 1976 Plenum Publishing Corporation, 227 West 17th Street, New York, N.Y. 10011. No part of this publication may be reproduced, stored in a retrieval system,or transmitted, in any form or by any means,electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written permissionof the publisher.

256

Kwan, Breauit, Umbenhauer,McMahon, and Duggan

necessary to postulate the existence of a "hypothetical organ," to accommodate the slower rate of appearance of I and I conjugate in the urine relative to the rate of disappearance of I from plasma. Finally, material balance considerations indicated that an oral dose of indomethacin was very nearly completely absorbed into the systemic circulation as I. There have subsequently appeared several reports (2-9) which suggest that the plasma half-life of I may be considerably longer than 2 hr (1), with values ranging as widely as 1.5-16 hr. For example, a mean half-life of 7.2 hr was estimated by Palmer et al. (5), who were able to extend their plasma sampling through 24 hr after administration using a mass fragmentographic assay. While their directly observed values are in good agreement with the properties of the "hypothetical organ" (1), they may also be manifestations of enterohepatic circulation, particularly in light of the high individual variability in apparent plasma half-life. Biliary excretion of I occurs to a varying degree in all laboratory animal species studied (10,11). Direct experimental evidence in man is limited to one cholecystotomized patient in whom 9 % of the dose was recovered in the bile after 48 hr (11). Indirectly, it can be inferred from the plasma concentration profiles of I in normal subjects and bile-occluded patients (9) that biliary clearance may be a significant component of plasma clearance. Thus, in view of this and the high efficiency of absorption, enterohepatic circulation of I is a possible alternative explanation for the variability in apparent plasma half-life and the observed differences in the kinetic behavior of I in plasma and urine. In the course of more recent disposition studies designed for the purpose of estimating the bioavailability of indomethacin in capsule and suppository dosage forms, data have been acquired to provide a more direct test of the enterohepatic circulation hypothesis and its relationship to the "hypothetical organ." Results of two such studies will be summarized and discussed in this report. The first was an investigation of the pharmacokinetics and the metabolic disposition of I following intravenous, oral, and rectal dosages of indomethacin-X4C. The relative bioavailability between commercial suppository and capsule dosage forms of indomethacin was studied in a second panel. It will be shown that the conclusions from the two studies are mutually consistent; it is hoped that a better understanding of the disposition of I ensues. EXPERIMENTAL In Study 1, six healthy volunteers each received single doses of indomethacin-2-14C by the oral (50 mg), rectal (50 mg), and intravenous (25 mg) routes at 1-week intervals according to a latin square design. Nominally,

Kinetics of Indomethacin Absorption, Elimination, and Enterohepatic Circulation in Man

257

each dose contained 25/~Ci of radioactivity. The actual dose administered orally and rectally was determined by chemical and radiometric analysis of a representative number of capsules and suppositories, respectively. Each vial of indomethacin for injection contained a known overage. Following injection, that which was not withdrawn from the vial and the rinsing from the syringe were combined such that the actual amount administered to each subject could be calculated by difference. Subjects received a standard meal (one 8-oz can of Metrecal, 8 oz of whole milk, and one medium-size apple) 30 rain prior to medication and 8 oz of water every 2 hr throughout the waking hours to ensure adequate urine output. Serial plasma samples were obtained at specified intervals for 8 hr after treatment. Total urine was collected for 2 days with timed aliquots taken for analysis. Feces were also collected quantitatively for 4 days after treatment. All specimens were kept frozen until analyzed by the isotope dilution procedure (1) for I, DMI, DBI, and DMBI, and their respective conjugates. In Study 2, 20 healthy male volunteers each received single 50-mg doses of indomethacin as a capsule (Indocin, 50 mg) and as a suppository (Indocin, 50 rag) immediately following a general hospital breakfast in a crossover design. At least 1 week elapsed between treatments. Water was consumed as described above. Serial plasma and urine samples were collected as before and kept frozen until analyzed fluorometrically for their contents of I and I conjugates. Plasma and urine specimens were assayed specifically for unchanged indomethacin and its conjugate, the latter after pretreatment with ]~-glucuronidase, by a modification of the method of Hucker et al. (12) whereby the fluorophores were terminally extracted into 0.2M Na2CO 3 containing 0.1 mMCuC12 in order to eliminate potential interferences by DMI. RESULTS

Study 1 Plasma specimens contain I, DMI, DBI, and insignificant amounts of DMBI, each in its unconjugated form. Individual plasma concentrations of I are shown in Table I. In general, peak plasma concentrations of I are similar or slightly higher following oral dosage as compared to rectal dosage, but peaks are achieved sooner following rectal administration. Mean concentrations of DMI and DBI are summarized in Figs. 1 and 2, respectively. Differences in their time course as a function of route appear to be qualitatively similar to those observed for I (Table I). Fractional urinary recoveries of I, DMI, DBI, and their respective conjugates are shown in Table II. DMBI and its conjugate are present only

i.v. p.o. p.r. i.v. p.o. p.r. i.v. p.o. p.r. i.v. p.o. p.r. i.v. p.o. p.r. i.v. p.o. p.r.

101

2.31 ---

2.05

1.85 --

-2.72

2.03

1.50 --

15

" P e a k p l a s m a levels, p.o. bPeak p l a s m a levels, p.r.

106

105

104

103

102

Route

Subject

0.09 0.45

0.04 0.24 -0.03 0.65

0.23 0.90

0.18 -0.02 0.18

20

-1.44 ---

1.39 ---1.04

1.49 --

-1.63

0.94

30

0.12 1.26 -0.62 1.09

0.77 1.36 -0.09 0.30

0.56 0.08 0.79

--

40

-0.81 -.... 1.03 ---

-1.02

1.16

-0.71

0.78

45 0.48 0.17 1.33 b 0.70 0.05 1.37 b 0.87 2.88 a 1.58 0.89 0.42 0.34 0.39 0.26 1.81 b 0.84 0.92 1.58 b

60

0.64 -----

-0.59 +-+ -0.30

0.64 --0.80

0.37 --

75

2.18 1.66 0.48 0.75 -0.78 1.57 -1.90" 1.51

0.53 1,22 -0.18 1.04

90

T i m e (min)

0.19 2.20" 1.14 0.36 1.13 0.65 0.39 1.92 1.67 b 0.40 1.67" 1.80 b 0.23 1.00 1.14 0.42 1.23 1.34

120 0.12 0.65 0.45 0.32 1.58 a 0.32 0.22 1.00 0.64 0.16 1.15 0.82 0.13 1.87" 0.55 0.24 0.90 1.01

180 0.11 0.23 0.24 0.20 0.89 0.28 0.12 0.61 0.54 0.11 0.55 0.52 0.11 1.I0 0.20 0.17 0.75 0.62

240 0.08 0.27 0.13 0.25 0.50 0.27 0.11 0.42 0.44 0.10 0.38 0.31 0.08 0.51 0.14 0.13 0.48 0.59

300

0.07 0.20 0.12 0.12 0.34 0.18 0.08 0.26 0.26 0.07 0.25 0.20 (). 10 0.32 0.11 0.10 0.22 0.39

360

0.05 0.17 0.08 0.08 0.33 0.16 0.08 0.18 0.26 0.07 0.25 0.11 0.06 0.26 0.17 0.09 0.29 0.20

480

T a b l e I. P l a s m a C o n c e n t r a t i o n s (#g/ml) of I n d o m e t h a c i n F o l l o w i n g Single I n t r a v e n o u s , O r a l , a n d Rectal Doses of I n d o m e t h a c i n - 2 - 1 4 C

10

~"

nn

Kinetics of Indomethacin Absorption, Elimination, and Enterohepatic Circulation in Man

I00= z

o

8 0 84

/

/

D

// z

6 0 84

o /

/

40

x.

c,J

\\

//

/

\ /

~.(~

20 e-e /

TIME,HR.

Fig. 1. Mean plasma concentration profiles of DMI following intravenous (~), oral (0), and rectal (C)) dosages of indomethacin- 14C.

140-

120o, IO0

z

80

9~

60

\\\\

40-

20/

-,,,

0

TIME,HR,

Fig. 2. Mean plasma concentration profiles of DBI following intravenous (~), oral (0), and rectal (O) dosages of indomethacin-14C.

259

Mean (free + conjugate)

106

105

104

103

i.v, p.o. p,r.

i.v, p,o p,r, i,v. p,o, p.r. i,v. p~o~ p.r. i.v. p.o. p.r. i,v. p,o. p,r. i.v. p.o. p,r.

101

102

Route

Subject

25.0 49,1 49.7

24.6 49.1 40.4 24.4 49,1 52.4 25.4 49.1 52.4 25.9 49.1 49.8 24,4 49.1 52.4 25.2 49.1 51.0

Dose (mg)

13.1 5.0 10.4 4.0 5,3 1.7 6.0 6.7 7.0 21.4 13.7 9.4 18,3 14,8 8.0 25.0 14.9 20.9

Free

31.8 27.4 24.0

15.8 25.9 24.5 27.1 9.6 10,7 34.8 39.7 28.7 9.8 8,4 8.1 7,0 6.6 6.9 8.6 13.6 7.5

Conjugate

I

13.2 11.1 16.0 5.2 3,0 7.3 11.6 13.5 9.0 I 1.5 7.2 7.4 7,9 5.5 2.5 4.1 5.5 5.9

Free

14.9 13,5 11.7

3.1 0.7 1,4 5,5 5.2 0 3.6 3.3 6.4 8.0 9.9 7,0 8,5 8.9 5,0 7.4 7.2 4.8

Conjugate

DMI

6.7 3.9 5.3 3.6 2.4 2.0 5.2 5.3 4.3 7.5 7.0 4.4 6.4 5.4 3.7 7.5 6.0 4.4

Free

Percentage of dose excreted in urine as

8,2 7,3 5,7

2.1 1.1 1~1 0~6 1,2 0.5 4,9 4.3 4.0 1.3 1.6 Z6 1.0 1.2 0,3 2.4 4.3 1.7

Conjugate

DBI

53,4 48.2 41.4

54.2 47.7 58.7 46,1 26.7 22,2 66.0 72.8 59.4 59.5 47.8 38,9 39.8 42.4 26.4 55.0 51.5 45.2

Total (%)

3.9 3,8 4.2

3.3 6.2 5.5 7.4 4.1 5.0 4.0 4.8 4.3 3.5 2.6 2.5 3,4 3.2 2.3 3.4 2.8 4.7

I:DBI

2.1 2,0 2.1

1.8 2,6 2.0 2,9 1.8 1.7 2.7 2.8 2.3 1,6 1.3 1.2 1.5 1.5 Z0 2.9 2.0 2,7

I:DMI

Ratios (free + conjugate)

Table II. Forty-Eight-Hour Urinary Recoveries of Indomethacin and Metabolites as a Function of Dosage Route

gll

| L

l

~-

m

,~

~u

III

ff

Kinetics of Indomethacin Absorption, Elimination, and Enterohepatic Circulation in Man

261

in minor quantities in urine and are not included in the table. It is evident from the ratios of I :DBI and I : D M I that there are no systematic changes in the biotransformation of indomethacin as a function of route. Differences within any given subject may be indicative of variations in renal clearance and/or the extent of enterohepatic circulation of some species between treatments. Apparent mean renal clearances of I, DMI, and DBI are given in Table III. These represent the ratio of the sum of the affected species and their conjugates excreted in the urine to the corresponding areas under the plasma concentration curves over the first 8 hr. In essence, they represent the mean clearance of the affected species from plasma through renal excretion and conjugation. These parameters are valid only when the plasma concentrations of the conjugate are negligible, suggesting that the conjugate(s) are cleared, whether renally or otherwise, as soon as they are formed. In other words, the apparent renal clearances shown in Table III represent not only the renal excretion of the affected species but also, at least in part, its clearance from plasma through conjugation. It is evident that the renal clearances for D M I and DBI vary more than those for I. A possible source of this variation may reside in the trapezoid approximations of area for D M I and DBI, the plasma concentrations of which are intermittently below the limits of detection. The fractional fecal recoveries of indomethacin and its metabolites are shown in Table IV. Despite the fact that compliance of some subjects appears questionable, therefore precluding any reasonable chance at material balance, there is no apparent suggestion that the disposition of indomethacin is dependent on the route of administration.

Table III. Individual Mean Renal Clearances (ml/min) of I, DMI, and DBI Following Intra-

venous, Oral, and Rectal Administration of Indomethacin Subject Chemical Dosage species route I

DMI

DBI

101

102

103

104

105

Mean

SD

i.v. p.o. p.r. i.v. p.o. p.r.

50.8 49.7 54.4 150.0 114.7 339.5

32.9 17.9 26.1 136.3 95.8 173.4

41.8 40.5 41.7 88.9 63.4 81.0

38.8 30.6 33.2 38.0 25.6 25.6 30.8 31.7 37.7 23.4 30.7 35.7 146.5 191.4 127.1 140.0 93.2 120.9 102.1 98.4 122.0 129.5 108.0 158.9

7.5 11.6 11.4 33.4 20.2 93.5

i.v. p.o. p.r.

195.3 72.4 67.5

75.3 40.6 97.1

50.9 29.2 30.3

150.1 90.4 67.5

53.9 22.5 25.3

156.1 44.6 31.0

106

129.0 126.1 54.2 55.2 57.4 58.5

262

Kwan, Bream't, Umbenhauer,McMahon, and Duggan

Table IV. Recovery of Indomethacin and Metabolites in the Feces as a Function of Dosage Route

Subject

Route

N u m b e r of samples on each of 4 days

101

i.v. p.o. p.r. i.v. p.o. p.r. i.v. p.o. p.r. i.v. p.o. p.r. i.v. p.o. p.r. i.v. p.o. p.r.

1-1-1-1 1-1-1-1 2-1-1-2 1-0-0-1 1-0-1-0 0-1-1-0 0-1-0-0 0-0-0-0 0-0-1-0 1-1-1-1 1-1-1-1 2-1-1-1 0-0-0-1 0-0-0-0 0-0-0-1 0-1-0-0 0-0-1-0 1-0-1-0

102

103

104

105

106

Mean

i.v. p.o. p.r.

Percentage of dose excreted in feces as I

DMI

DBI

DMBI

Total (%)

2.3 4.4 2.8 2.2 0.2 1.3 0.4 . 0.8 4.3 0.4 0.9 1.1 . 0.3 1.2 0.4 1.4

11.1 10.0 8.3 7.1 4.8 4.8 1.5

6.8 6.5 8.2 1.1 20.8 2.7 1.0

24.0 24.2 21.5 10.7 26.1 9.1 2.9

4.6 10.8 6.6 9.3 8.6

8.9 24.2 11.6 19.9 18.1

3.4 6.1 0.1 6.0

3.8 3.3 2.2 0.5 0.2 0.3 0 . 0.4 0.4 0.6 1.1 1.3 . 0.8 0.8 0 0.7

4.4 2.8 0.3 3.1

8.9 10.9 0.8 11.2

6.9 4.7 6.2

1.1 1.0 0.9

5.2 8.6 5.4

15.1 15.7 13.2

1.9 1.4 1.3

.

. 5.8 8.7 4.0 8.6 7.1

.

.

.

.

Study 2 Individual plasma concentrations of I following oral and rectal dosages are shown in Table V. Qualitatively and quantitatively, the results are in good agreement with those observed in Study 1. This is not surprising since the respective dosage forms in both studies are identical in their respective formula composition and conform with all physical and chemical specifications. Table VI summarizes the observed apparent renal clearances of I and the corresponding 48-hr urinary recoveries of I and its conjugate. Relative to Study 1, urinary recoveries from both oral and rectal treatments are lower, consistent with the observed differences in renal clearance between the two panels. The unusually low results following the rectal dosage in subject 211, in contrast to those for the other 19 subjects, appear suspect. They suggest the possibility that the suppository may have been prematurely expelled without being noticed. Except where noted, renal clearances of I were constant with time within a given treatment.

Kinetics of Indomethacin Absorption, Elimination, and Enterohepatic Circulation in Man

263

Table V. Plasma Concentrations (#g/ml) of Indomethacin Following Single 50-mg Doses as a Capsule or a Suppository Time (min)

TreatSubject

ment ~

20

40

60

90

120

180

240

300

360

480

720

201

C S C S C S C S C S C S C S C S C S C S C S C S C S C S C S C S C S C S C S C S

0.03 0.63 0 0.28 0.09 0.50 0.02 0.27 0 0.32 0 0 0 0..42 0 0.35 0.06 0.55 0.03 0.58 0.07 0.26 0.05 0.53 0.01 0.72 0.06 0.41 0 0.46 0 0.58 0 0.67 0 0.66 0 0.42 0 0.75

0.21 1.47 0 0.88 0.03 1.25 0.08 0.82 0 0.96 0 1.54 0 1.07 0 1.40 2.64c 1.22 0.02 1.25 0.04 0.20 0.26 1.45 0 1.69b 0.37 1.10 0.24 0.82 0 1.01 0.02 1.81 b 0.03 1.42 1.02 1.36 0.39 1.25

0.35 1.57b 0.01 1.13 ~ 0.10 1.36b 0.47 1.28 0 1.47 ~ 0 2.01 b 0.10 1.13 b 0 1.9& 1.94 1.32b 0.48 1.63 0.10 0.13 0.55 2.03 ~ 0.02 1.63 0.84 1.54b 0.55 1.25 0 1.56b 0.31 1.76 0.08 1.88~ 2.90~ 1.49 0.03 1.6&

0.65 1.51 0.08 0.99 0.22 0.95 1.22 1.30b 0.16 0.99 0 2.01 b 1.07 0.90 0 1.69 1.09 1.26 0.47 1.96b 0.62 0.08 1.06 2.01 0.88 1.49 1.05 ' 1.50 0.63 1.22 0.02 1.25 2.90 1.46 0.08 1.88 b 2.90' 1.58 b 0.39 1.60b

2.97 c 1.19 0.13 0.77 0.44 0.65 1.28 c 1.11 0.45 0.58 0 1.67 0.98 0.74 0.06 1.34 0.70 0.87 0.48 1.23 1.81 c 0.07 1.18 c 1.64 2.26 c 1.56 0.84 1.46 1.19c 1.53 b 0.11 1.10 2.95 c 0.92 0.49 1.62 2.39 1.30 0.60 1.17

2.19 0.88 0.96 0.46 1.45c 0.33 1.14 0.49 1.47 c 0.29 0.03 0.35 0.85 0.32 1.50 0.65 0.69 0.60 1.78 ~ 0.81 1.75 0.01 0.99 0.84 1.81 0.93 0.57 0.98 1.17 0.86 2.16~ 0.86 1.71 0.38 1.43 0.82 0.91 0.56 0.48 0.47

0.72 0.37 1.55c 0.25 1.34 0.18 1.20 0.25 0.73 0.83 1.26c 0.35 1.21 c 0.18 2.24c 0.39 0.44 0.33 0.92 0.44 0.67 0.12 1.11 0.46 1.23 0.41 0.50 0.55 -0.41 1.45 0.48 0.74 0.20 2.05' 0.44 0.62 0.49 1.03 0.22

0.35 0.08 0.58 0.20 0.37 0.07 0.71 0.16 0.37 0.23 1.24 0.27 0.90 0.10 1.12 0.25 0.25 0.25 0.43 0.24 0.35 0.04 0.50 0.28 0.56 0.29 0.35 0.55 0.52 0.20 0.68 0.20 0.50 0.17 1.54 0.29 0.44 0.56 1.77c 0.20

0.22 0.05 0.31 0.18 0.18 0.01 0.33 0.14 0.18 0.13 0.64 0.16 0.35 0.10 0.65 0.20 0.22 0.17 0.49 0.16 0.30 0.04 0.36 0.23 0.19 0.13 0.20 0.49 0.29 0.19 0.33 0.07 0.52 0.15 0.62 0.20 0.43 0.42 0.36 0.26

0.16 0 0.11 0.13 0.07 0.04 0.22 0.03 0.i1 0.10 0.09 0.06 0.22 0.02 0.24 0.11 0.12 0.05 0.20 0.03 0.24 0 0.16 0.06 0.11 0 0.14 0.40 0.19 0.15 0.05 0.04 0.24 0.07 0.26 0.14 0.15 0.26 0.07 0.10

0.24 0.10 0.20 0.09 0.04 0.04 0.16 0.02 0.16 0.08 0.15 0.03 0.16 0.02 0.19 0.06 0.11 0.13 0.14 0.05 0.17 0 0.06 0.04 0.10 0 0.08 0.12 0.24 0.18 0 0.03 0.19 0 0.15 0.09 0.26 0.12 0.13 0.

202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220

~C, capsule; S, suppository. bPeak plasma levels, p.r. cPeak plasma levels, p.o.

As in Study 1, earlier but generally lower plasma peaks were achieved with suppositories. Among subjects, plasma profiles appear more reproducible with respect to peak heights and peak times after suppository

264

Kwan, Breault, Umbenhauer, McMahon, and Duggan

Table Vl. Mean Renal Clearance and Total Urinary Recovery of Indomethacin and Its Conjugate Following Capsule and Suppository Dosages Renal clearance (ml/min)

Urinary recovery a (mg)

Subject

Capsule

Suppository

Capsule

201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220

25.1 11.4 18.4 24.6 34.8 45.8 16.4 18.9 25.7 20.9 --~ 13.1 20.2 30.8 25.7 18.6 7.8 29.8 21.9 13.4

37.8 32.2 23.4 26.1 27.3 31.6 17.0 10.1 20.7 24.7 --c 20.1 19.7 27.7 13.3 28.2 5.7 34.5 22.9 35.0

14.22 5.56 7.59 11.22 11.63 13.38 7.16 10.20 9.38 8.11 13.30 5.39 8.50 8.64 10.63 6.67 6.68 15.17 11.81 6.04

11.56 9.86 5.14 5.80 7.84 11.93 3.95 3.87 5.44 7.76 0.29 ~ 7.93 7.72 14.02 5.63 9.22 1.95 14.46 10.91 10.57

Mean a

22.3 (9.0)

24.1 (8.6)

9.37 (2.95)

8.19 (3.50)

(so)

Suppository

aThe sum of I + I conjugate.

bNot constant over time. CNo detectable urinary excretion from 2 to 36 hr. aSubject 211 not included.

administration. Hence absorption of I from suppositories appears to be both more rapid and more uniform. These results are also in excellent agreement with those reported in the literature (13-18). PHARMACOKINETIC ANALYSIS Kinetic analyses of the data were undertaken in an attempt to gain a greater understanding of the previously stated anomalies concerning the disposition of I. The analyses compared and contrasted two different conceptualizations of the observed time course with each other and with the estimates obtained by a model-independent technique. Initially, the results were analyzed on the premise that enterohepatic circulation of I was negligible following intravenous administration and that the observed differences in the plasma and urine time course could be attributed to the existence of a "hypothetical organ" (1). Alternatively, it was supposed that enterohepatic

Kinetics of Indomethacin Absorption, Elimination, and Enterohepafic Circulation in Man

265

circulation of I following all routes of administration could not be ignored and that the kinetic properties of the *'hypothetical organ" might be better identified with those of enterohepatic recycling. Finally, the effect of these alternative hypotheses on estimations of the bioavailability of I following capsule and suppository dosages were examined.

"Hypothetical Organ" It was shown previously (1) that the plasma concentration and urinary recovery data of I following intravenous administration may be adequately described by a two-compartment open model which includes a repository (termed the "hypothetical organ") for I or I conjugate between plasma and urine. This was necessary because the appearance of I and its conjugate in the urine is slower than that suggested by the product of the apparent plasma clearance and the fraction of dose recovered in the urine as I and I conjugate. Consequently, individual plasma concentration profiles following intravenous administration from Table I were fitted to a two-compartment open model. Pharmacokinetic parameters so obtained are shown in Table VII. For comparison, the last two columns of Table VII represent estimates of plasma clearance derived from plasma concentration data (k13V1) and from renal clearances and urinary recoveries (l?cJf), where l?cLr is the apparent renal clearance from Table III and f is the fraction of the dose recovered in the urine as I and I conjugate (Table II). It is evident that I is cleared more rapidly from plasma than would be supposed from urinary data and that this difference may be interpreted as a manifestation of the "hypothetical Table VII. Summary of Pharmacokinetic Parametersa or Indomethacin Disposition ("Hypothetical Organ" Alternative) Volume of distribution Plasma clearance (ml/min) (liters)

Rate constants (min -1)

~

Subject

k12

k21

k13

101 102 103 104 105 106

0~124 0.0187 0.0120 0.0071 0.0223 0.0123

0.0078 0.0128 0.0119 0.0076 0.0086 0.0103

0.0177 0.0167 0.0211 0.0157 0.0290 0.0171

VI 10.56 6.68 5.79 9.68 5.54 7.35

kl3V1

(/r

187.2 111.2 122.1 151.8 160.5 125.3

]75.8 105.8 102.5 124.4 120.9 98.8

model :

kl//

kl2 where k13 = kin + klo.

Kwan, Breauit; Umbenhauer, McMahon, and Duggan

266

organ." The cumulative amount of I being cleared via the "hypothetical organ" (H) as a function of time can be estimated by

H(t) =

~,,/f)

(k13V, --

Cp(tldt

(1)

the individual time courses of which are summarized in Table VIII. Equation 1 assumes that clearance from the "hypothetical organ" is also constant with time. The rate and extent of absorption from capsules and suppositories of indomethacin-~4C were calculated with the aid of disposition parameters for I through the consistent (19) application of the Loo-Riegelman (20) and Kwan-Till (21) methods. In every case, it was assumed that the nonrenal components of plasma clearance and the volume of distribution remained constant between treatments. Where indicated, adjustments in plasma clearance were made solely on the basis of observed changes in renal clearance, i.e., 9 n.i.v.t

Vel,p

:

" i.v.

Vcl,p

--

" i.v. Vcl,r

" n.i.v. -~- V c l , r

(2)

and

k'l 3 = V~,p " n . i . v d /1/1

(3)

9 n .i.v.t where Vcl.p and k'13 are, respectively, the adjusted plasma clearance and the adjusted elimination rate constant applicable to a given nonintravascular (n.i.v.) treatment. Individual absorption profiles of I following capsule and suppository dosages are shown in Table IX. The corresponding estimates of total absorption are summarized in Table X, which includes intermediate values in the 9 i.v. calculation. In particular, it should be noted that Vcl,p must be identified with k~3F1, instead of ~l,,/f, in order to be consistent with the model. In other words, estimates of F n'i'v" in Table X are not model-independent (21). The mean time courses of absorption are plotted in Fig. 3. It is evident that the initial absorption of I is more rapid following suppository administration, but more I is ultimately absorbed following oral dosage. By either route, there is a varying, but by no means insignificant, amount of absorption occurring beyond the eighth hour, the last plasma sample point. It is also evident that some explanation must be sought to account for estimates of rectal and oral absorption greater than the administered dose. The frequency of estimates of absorption (Table X)which are 9 n.i.v.t greater than 100 ~ suggests that the V~,p used in the calculation may be consistently too high relative to the actual plasma clearance for the affected treatments. If so, there should be systematic changes in the component parts of plasma clearance following nonintravascular and intravenous dosages

15 min

0.322 0.244 1.025 0.919 1.829 1,126

0.911 (0.582)

Subject

101 102 103 104 105 106

Mean (so)

1.452 (0.866)

0.528 0.407 1.626 1.581 2.713 1.858

30 min

1.811 (1.048)

0,675 0.504 2.014 2.072 3.258 2,344

45 min

2.073 (1.174)

0.780 0.566 2.311 2.464 3.600 2.715

60 min

2.268 (1.261)

0.852 0.625 2.556 2.765 3.806 3.007

75 min

2.679 (1.458)

0.991 0.754 3.057 3,368 4.277 3.629

120 min

3.001 (1,621)

1,095 0.873 3.402 3,796 4.696 4.143

180 min

3.199 (1.716)

1,173 0.963 3.592 4.013 4.986 4.468

240 min

Milligrams of I having been eliminated in

3.362 (1,769)

1.238 1.042 3.729 4.182 5.213 4.707

300 min

3.477 (1.846)

1.289 1.104 3.838 4.316 5.425 4.891

360 min

3.682 (1.963)

1.369 1.170 4.022 4.540 5.790 5.201

480 min

Table VIII. Estimates of the Cumulative A m o u n t s of Indomethacin Having Been Eliminated by Way of the "Hypothetical O r g a n " as a Function o f Time After Intravenous Dosage

=.

r

g~

L

o ,=

o ,=

0

0

Mean (sD)

106

105

104

103

p.r.

p.o.

p.o. p.r. p.o. p.r. p.o. p.r. p.o. p.r. p.o. p.r. p.o. p.r.

101

102

Route

Subject

1.1 (1.2) 7.2 (3.6)

0.3 5.7 0.4 2.6 3.3 13.2 0.9 5,4 0.4 8.8 1.5 7.6

20 min

5.4 (5.7) 19.6 (6.7)

0.4 21.2 1.6 14.2 13.2 25.6 2.5 8.8 2.2 24.9 12.2 22.9

40 min

16.2 (18.6) 36.9 (14.7)

4.8 55.3 1,7 29.9 51.0 37.7 I 1.0 12.4 5.7 45.7 22.9 40.2

60 min

30.5 (24.9) 53.4 (19.0)

18.6 80.1 4.7 38.1 68.9 53.7 17.5 27.0 19.6 65.5 53.8 55.7

90 min

56.1 (23.4) 65.1 (24.3)

78.1 101.5 24.6 39.6 84.5 68.2 53.3 36.7 35.5 77.7 60.4 67.0

120 min

79.6 (12.9) 73.8 (24.3)

88.7 108.3 59.2 39.1 95.2 72.5 74.1 55.3 85.8 85.9 74.5 81.4

180 min

87.7 (16.1) 76,1 (23,1)

86.2 107.8 67,9 39.6 99.0 76.9 77.2 62.9 113.1 83.5 83.0 85.9

240 min

Cumulative percentages of the dose absorbed in

90.2 (17.8) 77.5 (22.1)

88.9 105.0 67.0 41.4 101.1 80.8 80.0 65.4 118.4 80.8 85.9 91.8

300 min

89.9 (18.1) 77.9 (22.9)

90.2 104.2 65.3 41.7 101.4 81.9 80.7 66.5 118.0 79.3 84.0 93.7

360 min

Table IX. Individual Absorption Profiles of Indomethacin Following Oral and Rectal Administration

93.8 (17.4) 79.9 (21.6)

94.1 104.1 68.9 43.8 103.9 87.2 86.4 67,4 120.4 81.8 89.1 95.2

480 min

0.0176 0.0181 0.0145 0.0157 0.0209 0.0211 0.0143 0.0156 0.0281 0.0277 0.0167 0.0167

k'13

(min- 1)

L

Kinetics of Indomethacin Absorption, Elimination, and Enterohelmtic Circulation in Man

269

Table X, Individual Estimates of Total Absorption Following Oral and Rectal Dosages of

Indomethacin-14C Mean clearances (ml/min) Intravenous

Subject

Route

kl3Vla

VcI, ri.v.b "

101

i.v. p.o. p.r. l.v. p.o. p.r. i.v. p.o. p.r. i.v. p.o. p.r. i.v. p.o. p.r. i.v. p.o. p.r.

187.2

50.8

102 103 104 105 106

Mean (so)

111.7 122.1 151.8 160.5 125.3

Fraction of dose

Nonintravascular

Excreted Adsorbed

VcLp'..... n.i

UJD a

F,,.i.v.

49.7 54.4

186.1 190.8

0.309 0.349

1.157 1.225

17.9 26.1

96.7 104.9

0.149 0.124

0.805 0.498

40.5 41.7

120.8 122.0

0.464 0.357

1.385 1.044

25.6 37.7

138.6 150.7

0.221 0.175

1.195 0.700

25.6 23.4

155.5 153.3

0.214 0.149

1.297 0.974

30.8 30.7

t22.9 122.8

0.285 0.284

1.135 1.136

Vcl, r "n.i.v, b

32.9 41.8 38.8 30.6 33.2

p.o. p.r.

1.162 (0.199) 0.930 (0.277)

"From Table VII. bFrom Table III. ~By equation 2. aFractional recovery of I + I conjugate from Table II. since V~,p 9i.v. is the c o m m o n reference for the c o r r e s p o n d i n g 1/"iv'. S u p p o r t for this c a n n o t be found either in the renal clearance of I (Table III) or in the fractional distribution of metabolites in urine and feces (Tables II and IV) which are indices of the renal and metabolic c o m p o n e n t s of clearance, respectively. O n the contrary, there are other indications that the actual plasma clearance of I m a y be m o r e rapid than heretofore estimated. Experimental error in any given data point notwithstanding, the c u m u lative absorption profile (Table IX) should increase m o n o t o n i c a l l y with time. Systematic d o w n w a r d trends, particularly noticeable following rectal dosages in subjects 101 and 105, m a y be indicative of situations wherein the elimination rate being used in the material balance is t o o small to accomm o d a t e the observed decrements in p l a s m a c o n c e n t r a t i o n between contiguous sample points. In the present context, the implication is that the

270

Kwan, Breault, Umbenhauer, McMahon, and Duggan

120-

/----o-

I00 -

/

o--

/ I

8o-

o

60-

?

f

///

40 -

o.6 0

i

2

n 8

/

J

4tfl

TINE,HR.

Fig. 3. Mean time courses of I absorption following oral (O) and rectal (O) dosages of indomethacin-14C. (Based on the "hypothetical organ" alternative.)

proposed model may not be optimal in that the elimination parameters (k13 and k13F1) derived therefrom are too low. All of these problems may be circumvented by recognizing the possibility of enterohepatic circulation occurring to varying degrees regardless of the route of administration.

Enterohepatie Circulation Unfortunately, the timing of the urinary recovery data in Study 1 is such that a test for continuing absorption (19) at a given time cannot be attempted. Nevertheless, individual plasma concentration profiles from Table I are again fitted to a two-compartment open model with the supposition that some of the later sample points may include manifestations of enterohepatic cycling. This is accomplished by studying the plasma ti~e courses of I for all three treatments for each subject and selecting a slow disposition constant /~ which is consistent with the observed decrements between adjacent samples points. That is,/~ should be approximately equal to or greater than the steepest descending slope for all subsequent times following the intravenous dose and for all times following oral and rectal dosages. The assumptions are that the initial onset of reabsorption following intravenous administration may be variably delayed depending on gall bladder emptying and that the purely dispositional characteristics of I would be manifest (and therefore potentially sampleable) whenever absorption and/or reabsorption is not occurring. Pharmacokinetic parameters under the prescribed circumstances are shown in Table XI; they may be construed to be estimates of disposition in the bile-cannulated man and are

Kinetics of Indomethacin Absorption, Elimination, and Enterohepatic Circulation in Man

271

Table XI. Summary of Pharmacokinetic Parameters ~ of Indomethacin Disposition (Enterohepatic Circulation Alternative) Volume of distribution (liters)

Rate constants (min- 1) Subject

k* z

k~l

k* a

101 102 103 104 105 106

0.021t 0.0074 0.0389 0.0079 0.0259 0.0294

0.0398 0.0338 0.0368 0.0382 0.0221 0.0326

0.0279 0.0200 0.0314 0.0172 0.0387 0.0394

.

Plasma clearance (ml/min)

* *

V?

kl3V1

8.63 7.20 4.06 9.90 4.93 5.38

240.8 144.0 127.5 170.3 190.8 212.0

k*

where k~'3 = k*o + k*0.

"The model :

k,ol

k.,

distinguished from those in Table VII by an asterisk (*). The difference in fitting the same data to a two-compartment model under alternative assumptions concerning the existence of enterohepatic circulation is contrasted in Fig. 4. 30

30

(b)

(01

o 1.0

x

z

o

~o

05

~-

05

~o ua

w o2 co J

o_

o

Ol

o o

0.05

002

11

~

~

r TIME,HR

~

o05

002 TIME,HR.

Fig. 4. Typical fits of the same data to a two-compartment open model under alternative assumptions that enterohepatic circulation of I following intravenous dosage is (a) or is not (b) negligible (subject 101).

Kwan, Breault, Umbenhauer,McMahon, and Duggan

272

In the absence of enterohepatic cycling, material balance considerations (20,21) result in estimates of the time course of absorption. Since these techniques do not distinguish that which is absorbed for the first time and that which is reabsorbed after biliary secretion, their application in the presence of enterohepatic circulation yields estimates of the time course of the sum of both absorption and reabsorption. The mean time courses of the cumulative amount of I having entered the systemic circulation following intravenous, oral, and rectal dosages of indomethacin-14C are shown in Fig. 5. Individual profiles are summarized in Tables XII and XIII, which are, respectively, Loo-Riegelman (20) and Kwan-Till (21) estimates. As before, observed changes in renal clearance between treatments are assumed to be manifestations of variations in the renal component of elimination only, i.e., "xp

~

~

Vel, p .~_ k l 3 V 1 -

and

"i.v.

"x

(4)

Vcl,r + VeI,r

k*3 = fix, iT,'* -o,,~/-~

(5)

where the superscript x is identified with the intravenous, oral, or rectal dosage as the case may be. Even though the model parameters in Table XI are derived from the plasma concentration profiles following intravenous administration, some additional insight may be gained by performing a material balance calculation back upon itself. First, since those sample points used to construct the model are assumed to be free from the influence ofenterohepatic recirculation, 80/___.,,__

70-

c=

E6o-

z

o

/

o---

~,~_~5o:=~

40-

~

30-

/- _..~_.

i,l-,:l

i/

~

-

-~1 . . . .

41

.

.

.

.

m :~

20-

II I 111

I0-

k

&

i

8

i/1r

,;8

TIME,HR.

Fig. 5. Mean time courses of I having entered the systemic circulation following intravenous (0t), oral (0), and rectal (O) dosages of indomethacin-14C. (Based on the enterohepatic circulation alternative.)

p.r.

p.o.

0.0279 0.0278 0.0283 0.0200 0.0179 0.0191 0.0314 0.0311 0.0314 0.0172 0.0159 0.0171 0.0387 0.0377 0.0372 0.0394 0.0390 0.0389

k* 3 ( m i n - 1)

3.2 (1.4)

(0.4)

----

-

2.0 --0.2 1.5 --~ 1.2 5.3 -0.4 2.8 --0,2 4.4 -0.6 3,4

--

---0.5

.

20 rain

25.2 (1.7) --

-25.8 --25.4 --25.9 ---

25.0 . -22.1 --27.1

15 min

.

---

--

25.6 (1.1) --

23.6 --26.6 --26.0 --25,7 --26.2 ---

25.2

30 min

.

of Indomethacin

"Loo-Riegelman estimates. b Kwan-Till estimates from Table Xlll.

Mean (so)

106

105

104

103

i.v.

LV. p.o. p.r. i.v. p.o. p.r. i.v. p.o. p.r. i.v. p.o. p.r. i.v. p.o. p.r. i.v. p.o. p.r.

101

102

Route

Subject

Table XI[. Cumulative Amounts

9,6 (3.3)

(2.5)

--2.9

0.8 7.6 -5.7 12.4 -1.3 4.5 -1.1 12.9 -5.7 11.8

8.1

--

40 min

---

--

252 (2.9) --

-27.0 --26.1 ---

--. 19,4 --26.8 --25.4

26.5

45 rain

18.0 (6.4)

(8.2)

25,1 (2,3) 7.6

25.4 2.2 21.2 20.5 0.8 15.4 26.4 22,2 19.0 26.3 5.6 6.3 25.9 2.8 23.7 26.2 1-~.0 22.3

60 min

---

24.9 (1.9) --

25.3 -21.2 --26.8 --24.9 --25.6 --25.8 ---

75 min

26.5 (8.6)

(12.7)

--15.2

-8.7 31,6 -2.2 18.6 -33.1 27.1 -8.7 13.6 -9.4 34.3 -29.1 33.8

90 min

32.3 (10.9)

(11.5)

25.2 (1.7) 28,2

25.3 36.4 39,9 21,9 12.1 19.1 26,4 39.9 34.2 26.0 26.6 18.2 25.7 17.2 40,0 26.0 36.7 42.3

120 min

37.5 (12.5)

(7.3)

25.9 (0.8) 39.8

26.2 43.6 43.5 24.3 27.2 20.1 26.6 44.3 36.2 25.8 35.6 26.9 26.2 41.3 44.2 26.5 46.9 54.3

180 min

40.2 (13.4)

(9.6)

26.8 (0.7) 44.7

27.6 43,4 45.1 25.5 31.5 22.0 26.8 46.5 38.7 26.5 36.6 30.5 27.0 54.6 44.1 27.2 55.5 60.8

240 min

M i l l i g r a m s o f I h a v i n g e n t e r e d t h e s y s t e m i c c i r c u l a t i o n " in

42.6 (14.7)

(10.5)

27.8 (0.5) 47.6

28.7 46.7 46.1 27.8 33.4 24.1 27.5 48.5 41.5 27.3 38.8 32.1 27.7 57.9 44.4 28.0 60.6 67.4

300 min

44~,3 (15,8)

(10.6)

28.5 (0.6) 49,4

29.5 49.4 47.6 28.2 35,1 25.2 28,0 49.6 42.7 27.8 40.2 33.4 28.7 59.5 45.1 28.6 62.4 71.8

360 min

47.5 (16.9)

(11.1)

30.0 (0.7) 54,0

31.0 54.2 50.1 29.5 40.0 27.7 29.1 52.0 46.4 30.2 44.8 35.3 30.2 64.4 48.4 30.1 68.9 77.1

480 min

59,0 (22.8)

(13.9)

37.8 (8.3) 72.1

33.7 73.3 63.2 33.2 52.6 34.2 31.6 68.8 57.2 35.5 66.6 39.1 38.5 76.1 61.5 54.t 95.2 98.5

Total b (rag)

Having Entered the Systemic Circulation Following Intravenous, Oral, and Rectal Dosages of Indomethacin-14 C

m"

r

L

E"

274

Kwan, Breault, Umbenhauer, McMahon, and Duggan

Table XIII. Estimates of the Total Amounts of Indomethacin Having Entered the Systemic Circulation Following Intravenous, Oral, and Rectal Dosages of Indomethacin-14C Total entering systemic circulation Clearances (ml/min) Subject

Route

101

i.v. p.o. p.r. i.v. p.o. p.r. i.v. p.o. p.r. i.v. p.o. p.r. i.v. p.o. p.r. i.v. p.o. p.r.

102

103

104

105

106

Renal

Plasma

Amount excreted in urinec

9 x ,, V~l,~

"x b V~l,p

50.8 49.7 54.4 32.9 17.9 26.1 41.8 40.5 41.7 38.8 25.6 37.7 30.6 25.6 23.4 33.2 30.8 30.7

240.8 239.7 244.4 144.0 129.0 137.2 127.5 126.2 127.4 170.3 157.1 169.2 190.8 185.8 183.6 212.0 209.6 209.5

Amount (mg)

Fraction of dose

Relative to i.v.

(mg)

FXD x

Fx

FX/Fi.V.

7.109 15,172 14.100 7.588 7.319 6.498 10,363 22.782 18.707 8.081 10.851 8.715 6.173 10.507 7.808 8.467 13.994 14,484

33.7 73.3 63.2 33.2 52.6 34.2 31.6 68.8 57.2 35.5 66,6 39,1 38,5 76.1 61,5 54.1 95.2 98.5

1.370 1,492 1.568 1.361 1,072 0,652 1,244 1,401 1,092 1,369 1,356 0.785 1,577 1.553 1.169 2.146 1.939 1.932

1.000 1.089 1.145 1.000 0.788 0.479 1,000 1.126 0.878 1.000 0.991 0.573 1.000 0.985 0.741 1.000 0.904 0.900

aThe superscript x may be replaced by i.v., p.o., or p.r, as indicated. bBy equation 4. CThe sum of I and I conjugate.

the cumulative amount of I in the systemic circulation should be initially constant and equal to the dose. Such is indeed the case on the average (Fig. 5). Random deviations from constancy in a given individual profile can be interpreted as indices of the goodness of fit. A relatively poor fit was evident in the case of subject 102. Nevertheless, the selection of sample points for modeling appears adequate on the average. Second, while the onset of systematic departures from constancy is fixed by the initial assignments in modeling, the relative importance of a particular plasma concentration can be estimated in terms of the amount of I it represents. Finally, the material balance provides an initial estimate of the extent of enterohepatic cycling of I in man and its variability among individuals. The amount of I undergoing enterohepatic cycling can be estimated by the difference between the total amount of I having reached the systemic circulation and the injected dose, i.e., FiVD i'v' - D iv' from Table XIII. Among the six subjects, varying amounts (24-115 %) of the intravenous dose appear to have undergone biliary recycling. The cumulative amount of I having entered the systemic circulation at any given time following oral and rectal dosages has a different meaning from that after intravenous administration in that it is the composite of

Kinetics

of Indomethacin

Absorption,

Elimination,

and Enterohepatic Circulation in

Man

275

absorption and reabsorption. If the degree of enterohepatic recycling were constant for a given subject between treatments, then it would be possible to separate that fraction, g, of the dose absorbed from that which is reabsorbed, because g + (F ~'v - 1)g = F niv

(6)

Hence g

= F n ' i ' v ' / F i'v"

(7)

which are shown in the last column of Table XI!I. Since some of the entries for Fn.i.V./F i v are greater than 1.0, it is evident that for these subjects the assumption of constant degree of recycling does not hold. Finally, it should be noted that the previously cited systematic deviations from monotonicity in the cumulative time course have been virtually eliminated (Table XII). This provides additional support that the enterohepatic circulation model may be preferred over the "hypothetical organ" concept. By inference, therefore, the results appear to suggest that the kinetic properties of the "hypothetical organ" may be identified with those of the hepatoportal system.

Bioavailability Even though the Kwan-Till techniques (21) have been used in constructing Tables X and XIII, the estimates of F x therein are not entirely ~ i.v. ~ model-independent because the Vcl,p s employed are derived from model parameters, viz., k13V 1 and k13V 1. It seems appropriate, and perhaps informative, that these estimates should be contrasted with those obtained without reference to a model, since such model-independent solutions (21) are not influenced by manifestations of enterohepatic circulation. This would also provide a basis for the evaluation of data from Study 2 which does not include an intravenous treatment. Model-independent estimates of bioavailability of I following capsule and suppository dosages are shown in the third column of Table XIV. In contrast to previous estimates, these calculations are predicated on (/cl,r/f i v 9 i.v, as estimates of Vr Corresponding entries from the last columns of Tables XIII and X are tabulated in the fourth and fifth columns of Table XIV. It is apparent that there is excellent agreement between model-independent estimates and those modeled on enterohepatic circulation. Invariably, higher estimates of bioavailability result from the concept of a "hypothetical organ." This is not unexpected because the presumed existence of the "hypothetical organ" creates a greater relative difference between plasma and renal clearance. In other words, under the assumption of a "hypothetical organ," the observed renal clearance is too low relative to the estimated plasma clearance. It can be seen in the last column of Table XIV that if

276

Kwan, Breault, Umbenhauer, MeMahon, and Duggan

Table XIV. Estimates of Bioavailability (Percentage Relative to the Intravenous Dosage) from Capsule and Suppository Dosages of Indomethacin-t4C Model-dependent "Hypothetical organ" Subject

Dosage

101

Capsule

Suppository 102

Capsule

103

Capsule

104

Capsule

105

Capsule

106

Capsule

Mean

Capsule

Suppository Suppository Suppository Suppository Suppository (so)

Suppository a

'i.v.

Vr

--

~ i,v.

Vcl,,/f

i.v.

Modelindependenff

Enterohepatic circulationb

Unadjustedc

Adjustedd

108.6 115.1 75.6 47.0 115.9 87.7 96,0 57.2 96.9 72.4 89.2 89.1

108.9 114.5 78.8 47.9 112.6 87.8 99.1 57.3 98.5 74.1 90.4 90.0

115.7 122.5 80.5 49.8 138.5 104.4 119.5 70.4 129.7 97.4 113.5 113.6

108.6 115.1 75.6 47.0 115.9 87.6 96.0 57.6 96.9 72.4 93.9 94.1

97.0 (14.2) 78.1 (24.6)

98.1 (12.3) 78.6 (24.2)

116.2 (19.9) 93.0 (27.6)

97.8 (13.8) 79.0 (25.0)

9

bFrom Table XIII. CFrom Table X. d " i.v. V;L, is adjusted by accounting for the amount of I in the "hypothetical organ" (see text).

apparent renal clearances were calculated by summing the observed urinary recovery of I and its conjugates with the estimated quantities in the "hypothetical organ" (Table VIII) at corresponding times, the ensuing estimates of bioavailability would have been similar to those obtained by model-independent calculation and by the "enterohepatic recirculation" model. In anticipation of the fact that the evaluation of relative bioavailability between suppository and capsule dosage forms in Study 2 must rely on model-independent techniques, the data from Study 1 are reassessed by the method of Kwan and Till (21) with respect to the relative bioavailability between suppositories and capsules of indomethacin-14C ignoring the intravenous standard. Results of this analysis are shown in Table XV, which also includes for comparison estimates of relative bioavailability between capsules and suppositories of indomethacin-14C by all previous techniques. It is evident that similar estimates of relative bioavailability resulted in every case. Finally, Table XVI summarizes relative bioavailability between suppositories and capsules of indomethacin for individual subjects in Study 2. It is apparent that there is excellent agreement with the results of Study 1.

Kinetics of Indomethacin Absorption, Elimination, and Enterohelmtic Circulation in Man

277

TaMe XV. Bioavailability of Suppositories Relative to That of Capsules of Indomethacin-l*C (Percent) Intravenous standard b "Hypothetical organ" Subject

Capsule standarda

Modelindependent

Enterohepatic recirculation

Unadjusted

Adjusted

101 102 103 104 105 106

106.6 61.0 74.9 59.7 74.8 99.6

106.0 62.2 75.7 59.6 74.7 99.9

105.1 60.8 78.0 57.8 75.2 99.6

105.9 61.9 75.4 58.9 75.1 100. I

106.0 62.2 75.6 60.0 74.7 100.2

Mean (so)

79A (19.6)

79.7 (19.2)

79.4 (19.5)

79.6 (19.5)

79.8 (19.2)

aKwan-Till estimates using the capsule dosage as the standard. bRatios of suppository to capsule bioavailability from Table XIV.

Table XVI. Relative Bioavailability of Indomethacin Suppositories (s) to Capsules (c) (Study 2)

Urinary recovery

Bioavailability ratio

Mean clearances (ml/min)

Subject

F~f c

FSf s

l,;'~,,

[ ~'eel,p]r

201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220

0.284 0.111 0.152 0.224 0.233 0.268 0.143 0.204 0.188 0.162 0.266 0.108 0.170 0.173 0.213 0.133 0.134 0.303 0.236 0.121

0.231 0.197 0.103 0.116 0.157 0.239 0.079 0.077 0.109 0.155 0.006 0.159 0.154 0.280 0.113 0.184 0.039 0.289 0.218 0.211

25.1 11.4 18.4 24.6 34.8 45.8 16.4 18.9 25.7 20.9 ~ 13.1 20.2 30.8 25.7 18.6 7.8 29.8 21.9 13.4

88.3 102.5 121.2 109.6 149.6 171.2 114.5 92.6 137.0 128.9 --~ 121.5 118.8 178.2 120.9 139.4 58.4 98.2 92.7 110.9

~'~eSl,r 37.8 32.2 23.4 26.1 27.3 31.6 17.0 10.1 20.7 24.7 J 20.1 19.7 27.7 13.3 28.2 5.7 34.5 22.9 35.0

[ lYcSl,p];x

F~/F c

101.0 123.3 126.2 111.1 142.1 157.0 115.1 83.8 132.0 132.7 J 128.5 118.3 175.1 108.5 149.0 56.3 102.9 93.7 132.5

0.618 0.755 0.554 0.494 0.816 1.185 0.535 0.642 0.694 0.834 --~ 1.014 0.927 1.772 0.9]8 0.974 0.385 0.862 0.893 0.800

Mean

0.825

(so)

(0.305)

aNo reliable estimates possible.

278

Kwan, Breault, Umbenhauer,McMahon, and Duggan

DISCUSSION An attempt has been made to resolve several apparent contradictory observations concerning the disposition and bioavailability of indomethacin. In each case, the results appear to be reconcilable by recognizing the possible role of enterohepatic circulation. This hypothesis can be supported in several ways. First, indomethacin is absorbed efficiently by the oral route and is also cleared through the bile. Second, material balance considerations under the assumption of negligible enterohepatic circulation resulted in estimates of oral and rectal absorption frequently greater than the administered dose. This would be possible if a fraction of the dose were to enter the systemic circulation more than once. Plasma clearances estimated under the same assumption are not always consistent with the observed decrements between contiguous plasma concentration values. Much more satisfactory estimates resulted by identifying some of the data points with manifestations of enterohepatic cycling. The fact that absorption does not always exceed 100 70 and that the apparent deficiency in plasma clearance is detected only occasionally is also consistent with the sporadic and unpredictable nature of biliary discharge (and hence manifestations of reabsorption). Next, there are indications in every case of continuing absorption to varying degrees from 8 to 48 hr after treatment. Finally, estimates of absorption (and reabsorption) based on the enterohepatic circulation model are essentially identical to model-independent solutions. Given the recognition that the possibility of enterohepatic circulation cannot be ignored, it is estimated that a mean of 50 70 of an intravenous dose undergoes biliary recycling. Not surprisingly, individual estimates ranged from 24 to 115 70. Thus a given bioavailability estimate of greater than unity relative to the intravenous dose may simply mean that enterohepatic cycling is more extensive following that particular treatment. By the same token, the converse should be considered for relative bioavailabilities less than 1. Pharmacokinetic analyses of the data reveal certain similarities and contrasts between alternative conceptualizations of indomethacin disposition; they also provide the justification for the technique used to evaluate the relative bioavailability between suppositories and capsules. The excellent agreement between the two studies in turn reinforces the adequacy of the kinetic postulates. Differences in bioavailability between suppositories and capsules cannot be explained on the basis of rout,e dependence in metabolic disposition or part of the rectal dose not being absorbed as unchanged I. For if either were the case there would have been observed differences in the relative abundances of metabolites recovered in urine and/or feces among routes of

Kinetics of lndomethacin Absorption, Elimination, and Enterohepatic Circulation in Man

279

a d m i n i s t r a t i o n . O n the average, the lack of s a m e m a y also be indicative of similar ranges of e n t e r o h e p a t i c c i r c u l a t i o n by all routes. In view of its r a p i d i t y a n d u n i f o r m i t y relative to the oral dosage, a b s o r p t i o n of I from s u p p o s i t o r i e s a p p e a r s to be highly efficient. H o w e v e r , d a t a for subject 211 suggest that o c c a s i o n a l losses m a y be u n a v o i d a b l e in n o r m a l clinical use. In s u m m a r y , the v a r i a b i l i t y in a p p a r e n t p l a s m a half-life m a y be attrib u t e d to m a n i f e s t a t i o n s of b i l i a r y recirculation, in the a b s e n c e of the rea b s o r p t i v e c o m p o n e n t of which the d i s a p p e a r a n c e rate of I w o u l d be m u c h faster t h a n h e r e t o f o r e observed. Because of e n t e r o h e p a t i c cycling, b i o a v a i l ability is an index n o t only of a b s o r p t i o n b u t also of r e a b s o r p t i o n , the extent of which is a function n o t only of the a p p a r e n t bitiary c l e a r a n c e rate b u t also of the frequency of gall b l a d d e r e m p t y i n g a n d of the r e s u l t a n t p l a s m a c o n c e n t r a t i o n time course. Even t h o u g h i n d o m e t h a c i n a p p e a r s to be c a p a b l e of being c o m p l e t e l y a b s o r b e d from the rectum, in o r d i n a r y usage the bioa v a i l a b i l i t y from s u p p o s i t o r i e s is expected to be a b o u t 80 % of t h a t from i n t r a v e n o u s a n d c a p s u l e dosages.

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