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Colonoscopy in the investigation of drug absorption in healthy volunteers
0016·5107/85/3102·0071$02.00 GASTROINTESTINAL ENDOSCOPY Copyright © 1985 by the American Society for Gastrointestinal Endoscopy
Colonoscopy in the investigation of drug absorption in healthy volunteers c. H. Gleiter, MD, K.-H. Antonin, MD P. Sieck MD, J. Godbillon, MD W. Schbnleber, MD, H. Malchow, MD Ttlbingen, West Germany Rueil-Malmaison, France
In order to evaluate the absorptive capacity of the colonic mucosa, colonoscopy was used to investigate in six healthy volunteers the colonic absorption of the nonsteroidal anti-inflammatory drug diclofenac (Voltarene). Oral and colonic administration of 100 mg of diclofenac resulted in comparable peak plasma concentrations and areas under the plasma concentration time curves. The apparent relative availability of diclofenac from the colon compared to the oral form, which was assumed to be 100%, ranged from 54% to 109% with a mean of 78%. There was no difference in absorption between application of the drug in the cecum and in the splenic flexure. This new indication for colonoscopy proved to,.. be simple, well tolerated, and well suited for phase I studies with new drugs or formulations.
In the last few years many pharmaceutical prolonged-release preparations have been developed. These new formulations deliver drugs constantly along the entire gut, thus avoiding peak blood concentrations and related adverse effects. But the galenic improvement has raised new questions. Such preparations reach the large bowel, but it is not known whether and to what extent drugs are absorbed by the colonic mucosa, which is believed to absorb only water, electrolytes, and ammonia. Only few data from patients exist about drug absorption from the colon. i • 2 Performed by a skilled endoscopist, colonoscopy is a safe and quick examination. 3 The major complications are perforation (0.2%) and severe hemorrhage (0.04%); the death rate is 0.007%.4 We have used colonoscopy as a safe and simple means for studying drug absorption from different colonic segments. 5 To show the general applicability of this endoscopic technique, the measurement of colonic absorption of the nonsteroidal anti-inflammatory drug (NSAID) diclofenac was studied. Preliminary results have been published. 6
Special procedures
From the Human Plwrmacowgy Institute, Ciba-Geigy, TUbingen, West Germany; Bioplwrmaceutical Research Center, Ciba-Geigy, Rueil-Malmaison, France; and Department of Internal Medicine, University of TUbingen, TUbingen, West Germany. Reprint requests: C. H. Gleiter, MD, Human Plwrmacowgy Institute, Ciba-Geigy, Ob dem Himmelreich 7, D-7400 TUbingen, West Germany.
A study on the absorption of diclofenac-Na suspension from the cecum and splenic flexure compared to oral intake of tablets was performed in six healthy male volunteers. The age ranged between 20 and 30 years (mean, 26 years) and the body weight, between 67 and 94 kg (mean, 87 kg). Part I: After an overnight fast, 100 mg of diclofenac-Na (2 tablets of Voltaren'" 50, Ciba-Geigy) were swallowed in
VOLUME 31, NO.2, 1985
MATERIALS AND METHODS
General procedures
The study protocol was approved by the Ethics Committee, and informed written consent was obtained from each subject. All participants were found to be healthy by physical examination and laboratory checkup. None had a history of allergy or adverse reactions to NSAID or a history of gastrointestinal disease. No subject was allowed to take other medications for 1 week before and during the trial. The day before colonoscopy, only liquid meals until 2 p.m. were allowed. From this time until 10 p.m. the volunteers drank water or tea in large quantities (2 to 3 liters). Thereafter, all volunteers fasted until the procedure. The day before endoscopy at 8 a.m. each subject swallowed a laxative (X-Prep@, Mundipharma Limburg, West Germany; containing 30 ml of standardized extract of senna pods with 150 mg of senna glycosides A and B). One hour before endoscopy an enema (containing 1000 ml of water with 20 g of magnesium sulfate) was applied. No premedication or sedative was administered. The procedure was performed with a CF-LB 3 R colonoscope (Olympus).
71
the morning. Over the following 8 hours, eight blood samples were collected. Part II: After a drug-free interval of 2 weeks, colonoscopy was performed. Two tablets of diclofenac-Na were mechanically pulverized and suspended in 5 ml of distilled water. The suspension was exposed to ultrasound for 10 min. The suspension was applied through a thin catheter via the instrumentation channel of the endoscope. After injection the catheter was rinsed with 20 ml of distilled water. Following drug application into the cecal region in three volunteers and the region of the splenic flexure in three volunteers, blood samples were taken over 8 hours (Fig. 1). The plasma levels of diclofenac were measured by a sensitive and specific HPLC method. 7 RESULTS
Colonoscopy was generally well tolerated by the subjects. The time required to reach the cecum was 5 to 20 min (mean, 11 min). Fluoroscopy was used rarely for straightening the sigmoid colon. The following results were obtained: (1) Diclofenac concentrations were measurable in all subjects after
oral and colonic application. (2) The amount absorbed from the cecum was not different than that from the splenic flexure (Table 1). (3) Oral and colonic administration resulted in comparable peak plasma concentrations (Cmax ) and areas under the plasma concentration time curves between 0 and 8 hours (AUCo-Sh ) (Table 1, Figure 2). (4) The apparent relative availability (/rel) of diclofenac compared to an assumed 100% availability of the oral form ranged from 54% to 109% with a mean of 78% (Table 1). DISCUSSION
The large bowel has been regarded as not being able to absorb more than water and electrolytes. With the development of new sustained release drugs, the question arose whether and how the colon could absorb these drugs. The techniques employed in studying absorption in the large intestine have been reviewed recently.s Colonic perfusions by orally or rectally
I·J..
~
ClnII
__ ... lcolon
'_--v-~
.............. '"
········1
············1···- . .
t l°i o Figure 1. Illustration of drug application into the region of the splenic flexure (N = 3) (left) and into the cecal region (N = 3) (right).
1
3
2
4
time [hI
5
6
7
8
Figure 2. Plasma concentration time curve after oral and colonic application of 100 mg of diclofenac. Mean ± SEM (N
= 6).
Table 1. Comparison of pharmacokinetic data of oral versus colonic application of 100 mg of diclofenac· Oral application Volunteer no. b 1 2 3 4 5 6 Mean ± SD Median
Cmu (/lg/ml) 1.09 1.08 5.51 1.03 0.84 4.45 2.34 ± 2.08
t mu (hr) 3 2 1 3 3 2 2.5
AUC<>-8 (/lg/ ml x hr) 1.88 2.35 5.22 1.77 1.96 5.36 3.09 ± 1.72
Colonic application
Cmu (/lg/ml)
t.... (hr)
1.46 0.50 1.73 0.50 0.99 0.50 1.59 0.25 1.26 0.50 2.62 0.25 1.61 ± 0.56 0.50
AUC<>-8 (/lg/ml x hr) 1.66 2.24 2.87 1.94 1.84 3.09 2.27 ± 0.59
frel (%)
88 95 54 109 94 57 83 ± 22
• Cmu = peak plasma concentration; t mu = time needed to reach Cmu; AUC<>-8h = area under the plasma concentration time curve between 0 and 8 hours after application; frel = relative bioavailability. b Volunteers 1 to 3: drug application into the cecal region; volunteers 4 to 6: drug application into the region of the splenic flexure. 72
GASTROINTESTINAL ENDOSCOPY
passed tubes have several disadvantages: inflated luminal balloons may affect absorption, there is a delay and difficulty in positioning tubes, and the areas of absorbing mucosa are unknown. As yet, only a few studies have measured colonic absorption in patients by colonoscopy.l, 2 Ochs et al. l investigated the absorption of digoxin from the transverse colon in 12 patients. In eight patients with normal colonic mucosa a 24-hour urinary excretion of 17 ± 3.4% of the administered dose was obtained. The excretion in four patients with ulcerative colitis was only 1.7 ± 0.06%.1 Andersson et al. 2 studied the absorption of digoxin via a portal vein catheter. Two patients undergoing sigmoidoscopy were compared with four patients who were administered an aqueous solution orally. Six hours after application the group with oral administration showed a 64% absorption compared to the intrasigmoid administration which achieved 47% of the dose. 2 These data are difficult to interpret since the long pharmacokinetic half-life of digoxin had not been considered. In an earlier study this endoscopic technique was used the first time in healthy volunteers to evaluate the colonic absorption of oxprenolol. Compared to the oral application a mean relative bioavailability of approximately 80% was obtained via colonic absorption.s This corresponds to the {rei of 83% for diclofenac. The half-lives of oxprenolol and diclofenac are 1.5 and 2 hours, respectively. This corresponds to the values found in our studies for oxprenolol and diclofenac, whether applied orally or in the colon. As with the beta-blocker the site of application (cecum or splenic flexure) did not influence the results. This is an interesting finding because regional differences are well known in the absorptive capacity of the human colon concerning salt and water. The right side deals with large volumes of ileal effluent and absorbs salt avidly. It is said to be more permeable than the left side. The left side is supposedly less permeable but has a highly active absorptive capacity and, thus, is capable of maintaining the large concentration gradient generated across the mucosa. 9 The higher relative bioavailability of diclofenac in volunteer 4 after administration into the splenic flexure is probably due to colonic effluents in the rectum. Rectal absorption is known to bypass the liver. Thus, reduced hepatic first-pass effect could explain the higher amount of drug available systemically.
VOLUME 31, NO.2, 1985
The considerably longer time to peak (tmu ) after oral application of Voltaren@ 50 is caused by the enteric-coated preparation. It should be noted that the large intestine was well cleansed prior to endoscopy and that the trial does not correspond to physiological conditions. However, it is also generally accepted to study oral drug absorption on an empty upper intestinal tract. Prior cleansing enemas were shown not to influence the absorption of neomycin given by enema. IO Our own studies with sulfasalazine show an absolute bioavailability of 71 % for sulfapyridine absorbed from the large intestine, and these subjects were not pretreated to empty the bowel (P. Bieck, K.H. Antonin, and E. Hoffman, manuscript in preparation). ACKNOWLEDGMENT
The authors dedicate this article to Prof. Dr. W. Dolle on the occasion of his 60th birthday.
REFERENCES 1. Dehs H, Bodem G, Schafer PK, Kodrat G, Dengler HJ. Absorption of digoxin from the distal parts of the intestine in man. Eur J Clin PharmacoI1975;9:95-7. 2. Andersson KE, Nyberg L, Dencker H, Gothlin J. Absorption of digoxin in man after oral and intrasigmoid administration studied by portal vein catheterisation. Eur J Clin Pharmacol 1975;9:39-47. 3. Colin-Jones DG, Cockel R, Schiller KFR. Current endoscopic practice in the United Kingdom. Clin GastroenteroI1978;7:77586. 4. Friihmorgen P. Koloskopie-Ileoskopie. In: Domschke W, Koch H, eds. Diagnostik in der Gastroenterologie. New York: Thieme, 1979:118. 5. Antonin KH, Bieck PR, Scheurlen M, Jedrychowski M, Malchow H. Colonoscopy as a means to study in humans drug absorption (oxprenolol) from different colonic segments. Br J Clin Pharmacol (in press). 6. Bieck P, Antonin KH, Gleiter C, Godbillon J, Malchow H. Measurements of diclofenac absorption from human colon by means of colonoscopy. International Symposium on Gastroenterology, Bologna, Italy, April 7-8, 1983. 7. Godbillon J, Gauron S, Metayer JP. High performance liquid chromatographic determination of diclofenac and its monohydroxylated metabolites in biological fluids. J Chromatogr Biomed Appl (in press). 8. Shields R. Absorption from the human colon. In: Duthie HL, Wormsley KG, eds. Scientific basis of gastroenterology. New York: Churchill-Livingstone, 1979:398--414. 9. Hawker PC, Turnberg LA. In: Alexander-Williams J, Binder HJ, eds. Large intestine. London: Butterworth, 1983:1-15. 10. Breen KJ, Bryant RE, Levinson JD, Schenker S. Neomycin absorption in man. Studies of oral and 'enema administration and effect of intestinal ulceration. Ann Intern Med 1972; 76:211-8.
73
Colonoscopy in the investigation of drug absorption in healthy volunteers c. H. Gleiter, MD, K.-H. Antonin, MD P. Sieck MD, J. Godbillon, MD W. Schbnleber, MD, H. Malchow, MD Ttlbingen, West Germany Rueil-Malmaison, France
In order to evaluate the absorptive capacity of the colonic mucosa, colonoscopy was used to investigate in six healthy volunteers the colonic absorption of the nonsteroidal anti-inflammatory drug diclofenac (Voltarene). Oral and colonic administration of 100 mg of diclofenac resulted in comparable peak plasma concentrations and areas under the plasma concentration time curves. The apparent relative availability of diclofenac from the colon compared to the oral form, which was assumed to be 100%, ranged from 54% to 109% with a mean of 78%. There was no difference in absorption between application of the drug in the cecum and in the splenic flexure. This new indication for colonoscopy proved to,.. be simple, well tolerated, and well suited for phase I studies with new drugs or formulations.
In the last few years many pharmaceutical prolonged-release preparations have been developed. These new formulations deliver drugs constantly along the entire gut, thus avoiding peak blood concentrations and related adverse effects. But the galenic improvement has raised new questions. Such preparations reach the large bowel, but it is not known whether and to what extent drugs are absorbed by the colonic mucosa, which is believed to absorb only water, electrolytes, and ammonia. Only few data from patients exist about drug absorption from the colon. i • 2 Performed by a skilled endoscopist, colonoscopy is a safe and quick examination. 3 The major complications are perforation (0.2%) and severe hemorrhage (0.04%); the death rate is 0.007%.4 We have used colonoscopy as a safe and simple means for studying drug absorption from different colonic segments. 5 To show the general applicability of this endoscopic technique, the measurement of colonic absorption of the nonsteroidal anti-inflammatory drug (NSAID) diclofenac was studied. Preliminary results have been published. 6
Special procedures
From the Human Plwrmacowgy Institute, Ciba-Geigy, TUbingen, West Germany; Bioplwrmaceutical Research Center, Ciba-Geigy, Rueil-Malmaison, France; and Department of Internal Medicine, University of TUbingen, TUbingen, West Germany. Reprint requests: C. H. Gleiter, MD, Human Plwrmacowgy Institute, Ciba-Geigy, Ob dem Himmelreich 7, D-7400 TUbingen, West Germany.
A study on the absorption of diclofenac-Na suspension from the cecum and splenic flexure compared to oral intake of tablets was performed in six healthy male volunteers. The age ranged between 20 and 30 years (mean, 26 years) and the body weight, between 67 and 94 kg (mean, 87 kg). Part I: After an overnight fast, 100 mg of diclofenac-Na (2 tablets of Voltaren'" 50, Ciba-Geigy) were swallowed in
VOLUME 31, NO.2, 1985
MATERIALS AND METHODS
General procedures
The study protocol was approved by the Ethics Committee, and informed written consent was obtained from each subject. All participants were found to be healthy by physical examination and laboratory checkup. None had a history of allergy or adverse reactions to NSAID or a history of gastrointestinal disease. No subject was allowed to take other medications for 1 week before and during the trial. The day before colonoscopy, only liquid meals until 2 p.m. were allowed. From this time until 10 p.m. the volunteers drank water or tea in large quantities (2 to 3 liters). Thereafter, all volunteers fasted until the procedure. The day before endoscopy at 8 a.m. each subject swallowed a laxative (X-Prep@, Mundipharma Limburg, West Germany; containing 30 ml of standardized extract of senna pods with 150 mg of senna glycosides A and B). One hour before endoscopy an enema (containing 1000 ml of water with 20 g of magnesium sulfate) was applied. No premedication or sedative was administered. The procedure was performed with a CF-LB 3 R colonoscope (Olympus).
71
the morning. Over the following 8 hours, eight blood samples were collected. Part II: After a drug-free interval of 2 weeks, colonoscopy was performed. Two tablets of diclofenac-Na were mechanically pulverized and suspended in 5 ml of distilled water. The suspension was exposed to ultrasound for 10 min. The suspension was applied through a thin catheter via the instrumentation channel of the endoscope. After injection the catheter was rinsed with 20 ml of distilled water. Following drug application into the cecal region in three volunteers and the region of the splenic flexure in three volunteers, blood samples were taken over 8 hours (Fig. 1). The plasma levels of diclofenac were measured by a sensitive and specific HPLC method. 7 RESULTS
Colonoscopy was generally well tolerated by the subjects. The time required to reach the cecum was 5 to 20 min (mean, 11 min). Fluoroscopy was used rarely for straightening the sigmoid colon. The following results were obtained: (1) Diclofenac concentrations were measurable in all subjects after
oral and colonic application. (2) The amount absorbed from the cecum was not different than that from the splenic flexure (Table 1). (3) Oral and colonic administration resulted in comparable peak plasma concentrations (Cmax ) and areas under the plasma concentration time curves between 0 and 8 hours (AUCo-Sh ) (Table 1, Figure 2). (4) The apparent relative availability (/rel) of diclofenac compared to an assumed 100% availability of the oral form ranged from 54% to 109% with a mean of 78% (Table 1). DISCUSSION
The large bowel has been regarded as not being able to absorb more than water and electrolytes. With the development of new sustained release drugs, the question arose whether and how the colon could absorb these drugs. The techniques employed in studying absorption in the large intestine have been reviewed recently.s Colonic perfusions by orally or rectally
I·J..
~
ClnII
__ ... lcolon
'_--v-~
.............. '"
········1
············1···- . .
t l°i o Figure 1. Illustration of drug application into the region of the splenic flexure (N = 3) (left) and into the cecal region (N = 3) (right).
1
3
2
4
time [hI
5
6
7
8
Figure 2. Plasma concentration time curve after oral and colonic application of 100 mg of diclofenac. Mean ± SEM (N
= 6).
Table 1. Comparison of pharmacokinetic data of oral versus colonic application of 100 mg of diclofenac· Oral application Volunteer no. b 1 2 3 4 5 6 Mean ± SD Median
Cmu (/lg/ml) 1.09 1.08 5.51 1.03 0.84 4.45 2.34 ± 2.08
t mu (hr) 3 2 1 3 3 2 2.5
AUC<>-8 (/lg/ ml x hr) 1.88 2.35 5.22 1.77 1.96 5.36 3.09 ± 1.72
Colonic application
Cmu (/lg/ml)
t.... (hr)
1.46 0.50 1.73 0.50 0.99 0.50 1.59 0.25 1.26 0.50 2.62 0.25 1.61 ± 0.56 0.50
AUC<>-8 (/lg/ml x hr) 1.66 2.24 2.87 1.94 1.84 3.09 2.27 ± 0.59
frel (%)
88 95 54 109 94 57 83 ± 22
• Cmu = peak plasma concentration; t mu = time needed to reach Cmu; AUC<>-8h = area under the plasma concentration time curve between 0 and 8 hours after application; frel = relative bioavailability. b Volunteers 1 to 3: drug application into the cecal region; volunteers 4 to 6: drug application into the region of the splenic flexure. 72
GASTROINTESTINAL ENDOSCOPY
passed tubes have several disadvantages: inflated luminal balloons may affect absorption, there is a delay and difficulty in positioning tubes, and the areas of absorbing mucosa are unknown. As yet, only a few studies have measured colonic absorption in patients by colonoscopy.l, 2 Ochs et al. l investigated the absorption of digoxin from the transverse colon in 12 patients. In eight patients with normal colonic mucosa a 24-hour urinary excretion of 17 ± 3.4% of the administered dose was obtained. The excretion in four patients with ulcerative colitis was only 1.7 ± 0.06%.1 Andersson et al. 2 studied the absorption of digoxin via a portal vein catheter. Two patients undergoing sigmoidoscopy were compared with four patients who were administered an aqueous solution orally. Six hours after application the group with oral administration showed a 64% absorption compared to the intrasigmoid administration which achieved 47% of the dose. 2 These data are difficult to interpret since the long pharmacokinetic half-life of digoxin had not been considered. In an earlier study this endoscopic technique was used the first time in healthy volunteers to evaluate the colonic absorption of oxprenolol. Compared to the oral application a mean relative bioavailability of approximately 80% was obtained via colonic absorption.s This corresponds to the {rei of 83% for diclofenac. The half-lives of oxprenolol and diclofenac are 1.5 and 2 hours, respectively. This corresponds to the values found in our studies for oxprenolol and diclofenac, whether applied orally or in the colon. As with the beta-blocker the site of application (cecum or splenic flexure) did not influence the results. This is an interesting finding because regional differences are well known in the absorptive capacity of the human colon concerning salt and water. The right side deals with large volumes of ileal effluent and absorbs salt avidly. It is said to be more permeable than the left side. The left side is supposedly less permeable but has a highly active absorptive capacity and, thus, is capable of maintaining the large concentration gradient generated across the mucosa. 9 The higher relative bioavailability of diclofenac in volunteer 4 after administration into the splenic flexure is probably due to colonic effluents in the rectum. Rectal absorption is known to bypass the liver. Thus, reduced hepatic first-pass effect could explain the higher amount of drug available systemically.
VOLUME 31, NO.2, 1985
The considerably longer time to peak (tmu ) after oral application of Voltaren@ 50 is caused by the enteric-coated preparation. It should be noted that the large intestine was well cleansed prior to endoscopy and that the trial does not correspond to physiological conditions. However, it is also generally accepted to study oral drug absorption on an empty upper intestinal tract. Prior cleansing enemas were shown not to influence the absorption of neomycin given by enema. IO Our own studies with sulfasalazine show an absolute bioavailability of 71 % for sulfapyridine absorbed from the large intestine, and these subjects were not pretreated to empty the bowel (P. Bieck, K.H. Antonin, and E. Hoffman, manuscript in preparation). ACKNOWLEDGMENT
The authors dedicate this article to Prof. Dr. W. Dolle on the occasion of his 60th birthday.
REFERENCES 1. Dehs H, Bodem G, Schafer PK, Kodrat G, Dengler HJ. Absorption of digoxin from the distal parts of the intestine in man. Eur J Clin PharmacoI1975;9:95-7. 2. Andersson KE, Nyberg L, Dencker H, Gothlin J. Absorption of digoxin in man after oral and intrasigmoid administration studied by portal vein catheterisation. Eur J Clin Pharmacol 1975;9:39-47. 3. Colin-Jones DG, Cockel R, Schiller KFR. Current endoscopic practice in the United Kingdom. Clin GastroenteroI1978;7:77586. 4. Friihmorgen P. Koloskopie-Ileoskopie. In: Domschke W, Koch H, eds. Diagnostik in der Gastroenterologie. New York: Thieme, 1979:118. 5. Antonin KH, Bieck PR, Scheurlen M, Jedrychowski M, Malchow H. Colonoscopy as a means to study in humans drug absorption (oxprenolol) from different colonic segments. Br J Clin Pharmacol (in press). 6. Bieck P, Antonin KH, Gleiter C, Godbillon J, Malchow H. Measurements of diclofenac absorption from human colon by means of colonoscopy. International Symposium on Gastroenterology, Bologna, Italy, April 7-8, 1983. 7. Godbillon J, Gauron S, Metayer JP. High performance liquid chromatographic determination of diclofenac and its monohydroxylated metabolites in biological fluids. J Chromatogr Biomed Appl (in press). 8. Shields R. Absorption from the human colon. In: Duthie HL, Wormsley KG, eds. Scientific basis of gastroenterology. New York: Churchill-Livingstone, 1979:398--414. 9. Hawker PC, Turnberg LA. In: Alexander-Williams J, Binder HJ, eds. Large intestine. London: Butterworth, 1983:1-15. 10. Breen KJ, Bryant RE, Levinson JD, Schenker S. Neomycin absorption in man. Studies of oral and 'enema administration and effect of intestinal ulceration. Ann Intern Med 1972; 76:211-8.
73