Letter to the Editors 597
Orally Administered Liposomes Prepared with Egg Phosphatidylcholine and Stearylamine: Possible Destruction in Rat Intestinal Wall
Sir, Dr. Fukunaga and colleagues have observed that liposome-entrapped calcitonin administered orally to fasting male rats resulted in a light hypocalcemia when the phospholipids layers contained stearylamine (Fukunaga, Miller and Deftos 1991). However, even with this improvement, the hypocalcemia measured was much lighter than when the hormone was injected (Dupuy, Peuchant, Vitiello, Jensen, Baghdiantz and Blanquet 1983; Dupuy 1983). The advantage in oral administration of this peptide led us to examine why it was inefficient. The Fukunaga method tried to benefit from the protective effect of liposomes, but this supposes that these particles are well preserved, not only in the lumen of the gastrointestinal tract but also in its wall where proteolytic enzymes are found (Lee 1988). Measurements of blood and faecal radioactivity in rats orally loaded with liposome-entrapped 125iodinated calcitonin, or 111indium would indicate if liposomes are preserved. The pharmacokinetics of these two products have been known for a long time: When liposomes are disrupted in the intestinal wall, indium is directly excreted in the intestinal lumen (Valberg, Flanagan, Haist, Frei and Chamberlin 1981) and iodine, released by the lysed calcitonin, is rapidly diluted in the "iodine space" of the animals (Wayne, Koutras and Alexander 1964; Scarpace, Parthemore and Deftos 1978).
and loaded with
with 111In (Mauk and Gamble 1979). After oral administration of free or liposome-entrapped indium, no radioactivity was detected in the blood for 24 hours (Fig. 1). In the faeces, radioactivity was maximal on the first and the third days in rats loaded with free indium and liposome-entrapped indium, respectively (Fig. 2). Hypocalcemia following liposome-entrapped calcitonin indicated that some of the hormone crossed the intestinal wall. However, the time for radioactivity to disappear from blood of rats loaded with the hormone encapsulated or not in liposomes was the same (Fig. 1). These results strongly suggest that most of the hormone was lysed so the liposomes would have to be more resistant, in our hands, to benefit from for the Fukunaga effect. Answer of the Authors: Sir, we appreciate the efforts of Arien and colleagues to elucidate some of the mechanisms involved in our studies of liposomal calcitonin (L-CT). We acknowledged in our manuscript that the changes in calcium following the administration of the L-CT were small and transient. The work of Arien et al., helps to explain, at least in part, this "light" effect. We hope that further experimentation will allow the promise of liposomal drug delivery to become clinically valuable.
Liposomes were prepared as proposed by Fukunaga I calcitonin (Fukunaga, Miller and Deftos 1991), or
125
Fig. 1 Clearance of radioactivity in 0.2 ml of blood withdrawn from the tail of rats. Left: fasting male rats (300 g) were fed with free 111lndium chloride (a) or liposome-entrapped Nitrilotriacetate 111 In (105cpm) (b). Right: fasting male rats (300 g) were fed with free (c) or liposome-entrapped125Icalcitonin (105 cpm) (d).
Fig. 2 Clearance of radioactivities in faeces (1 g) of male rats for 5 days after oral administration of free 111 lndium Chloride (105cpm) (0) or liposome-entrapped Nitrilotriacetate 111 Indium (105 cpm) (El).
Horm. metab. Res. 24 (1992) 597-598 © Georg Thieme Verlag Stuttgart • New York
Received: 16 July 1992
Accepted: 28 August 1992
Downloaded by: University of Pennsylvania Libraries. Copyrighted material.
A. Arien l, C. Goigoux 1, B. Basse-Cathalinat2 and B. Dupuy 1 1 INSERM-U.306 and 2 Nuclear Medicine Pellegrin Hospital, Bordeaux, France
Harm, metab. Res. 24 (1992)
A. Arien, C. Goigoux, B. Basse-Cathalinat and B. Dupuy
References Requests for reprints should be addressed to: Dupuy B.: Biomed. Pharmacother. 37: 54-57 (1983) Dupuy B., E. Peuchant, S. Vitiello, R. Jensen, A. Baghdiantz, P. Blan-B. Dupuy quet: Experientia 39: 294-296 (1983) INSERM-U 306 Fukunaga, M., M. M. Miller, L. J. Deftos: Horm. Metab. Res. 23: 166—Universite de Bordeaux II 167 (1991) 146 Rue Leo Saignat Lee, V. H. L.: Crit. Rev. Ther. Drug Carrier Syst. 5: 2, 69-97 (1988) F-33076 Bordeaux cedex Mauk, M. R., R. C. Gamble: Anal. Biochem. 94: 302-307 (1979) France Scarpace, P J, J. G Parthemore, L. J. Deftos: Endocrinology 103: 1, 128-132(1978) Leonard J. Deftos, M. D. Valberg, L. S., P. R. Flanagan, J. Haist, J. V. Frei, M. J. Chamberlain: San Diego VA Medical Center Clin. Invest. Med. 4: 2, 103-108 (1981) Mail Code V-l 11C Wayne E. J., D. A. Koutras, W. D. Alexander: In: Clinical Aspects of LaJolla, C.A. 92161 Iodine Metabolism, Blackwell Scientific Publications, Oxford U.S.A. (1964), pp. 3-37
Downloaded by: University of Pennsylvania Libraries. Copyrighted material.
598
Orally Administered Liposomes Prepared with Egg Phosphatidylcholine and Stearylamine: Possible Destruction in Rat Intestinal Wall
Sir, Dr. Fukunaga and colleagues have observed that liposome-entrapped calcitonin administered orally to fasting male rats resulted in a light hypocalcemia when the phospholipids layers contained stearylamine (Fukunaga, Miller and Deftos 1991). However, even with this improvement, the hypocalcemia measured was much lighter than when the hormone was injected (Dupuy, Peuchant, Vitiello, Jensen, Baghdiantz and Blanquet 1983; Dupuy 1983). The advantage in oral administration of this peptide led us to examine why it was inefficient. The Fukunaga method tried to benefit from the protective effect of liposomes, but this supposes that these particles are well preserved, not only in the lumen of the gastrointestinal tract but also in its wall where proteolytic enzymes are found (Lee 1988). Measurements of blood and faecal radioactivity in rats orally loaded with liposome-entrapped 125iodinated calcitonin, or 111indium would indicate if liposomes are preserved. The pharmacokinetics of these two products have been known for a long time: When liposomes are disrupted in the intestinal wall, indium is directly excreted in the intestinal lumen (Valberg, Flanagan, Haist, Frei and Chamberlin 1981) and iodine, released by the lysed calcitonin, is rapidly diluted in the "iodine space" of the animals (Wayne, Koutras and Alexander 1964; Scarpace, Parthemore and Deftos 1978).
and loaded with
with 111In (Mauk and Gamble 1979). After oral administration of free or liposome-entrapped indium, no radioactivity was detected in the blood for 24 hours (Fig. 1). In the faeces, radioactivity was maximal on the first and the third days in rats loaded with free indium and liposome-entrapped indium, respectively (Fig. 2). Hypocalcemia following liposome-entrapped calcitonin indicated that some of the hormone crossed the intestinal wall. However, the time for radioactivity to disappear from blood of rats loaded with the hormone encapsulated or not in liposomes was the same (Fig. 1). These results strongly suggest that most of the hormone was lysed so the liposomes would have to be more resistant, in our hands, to benefit from for the Fukunaga effect. Answer of the Authors: Sir, we appreciate the efforts of Arien and colleagues to elucidate some of the mechanisms involved in our studies of liposomal calcitonin (L-CT). We acknowledged in our manuscript that the changes in calcium following the administration of the L-CT were small and transient. The work of Arien et al., helps to explain, at least in part, this "light" effect. We hope that further experimentation will allow the promise of liposomal drug delivery to become clinically valuable.
Liposomes were prepared as proposed by Fukunaga I calcitonin (Fukunaga, Miller and Deftos 1991), or
125
Fig. 1 Clearance of radioactivity in 0.2 ml of blood withdrawn from the tail of rats. Left: fasting male rats (300 g) were fed with free 111lndium chloride (a) or liposome-entrapped Nitrilotriacetate 111 In (105cpm) (b). Right: fasting male rats (300 g) were fed with free (c) or liposome-entrapped125Icalcitonin (105 cpm) (d).
Fig. 2 Clearance of radioactivities in faeces (1 g) of male rats for 5 days after oral administration of free 111 lndium Chloride (105cpm) (0) or liposome-entrapped Nitrilotriacetate 111 Indium (105 cpm) (El).
Horm. metab. Res. 24 (1992) 597-598 © Georg Thieme Verlag Stuttgart • New York
Received: 16 July 1992
Accepted: 28 August 1992
Downloaded by: University of Pennsylvania Libraries. Copyrighted material.
A. Arien l, C. Goigoux 1, B. Basse-Cathalinat2 and B. Dupuy 1 1 INSERM-U.306 and 2 Nuclear Medicine Pellegrin Hospital, Bordeaux, France
Harm, metab. Res. 24 (1992)
A. Arien, C. Goigoux, B. Basse-Cathalinat and B. Dupuy
References Requests for reprints should be addressed to: Dupuy B.: Biomed. Pharmacother. 37: 54-57 (1983) Dupuy B., E. Peuchant, S. Vitiello, R. Jensen, A. Baghdiantz, P. Blan-B. Dupuy quet: Experientia 39: 294-296 (1983) INSERM-U 306 Fukunaga, M., M. M. Miller, L. J. Deftos: Horm. Metab. Res. 23: 166—Universite de Bordeaux II 167 (1991) 146 Rue Leo Saignat Lee, V. H. L.: Crit. Rev. Ther. Drug Carrier Syst. 5: 2, 69-97 (1988) F-33076 Bordeaux cedex Mauk, M. R., R. C. Gamble: Anal. Biochem. 94: 302-307 (1979) France Scarpace, P J, J. G Parthemore, L. J. Deftos: Endocrinology 103: 1, 128-132(1978) Leonard J. Deftos, M. D. Valberg, L. S., P. R. Flanagan, J. Haist, J. V. Frei, M. J. Chamberlain: San Diego VA Medical Center Clin. Invest. Med. 4: 2, 103-108 (1981) Mail Code V-l 11C Wayne E. J., D. A. Koutras, W. D. Alexander: In: Clinical Aspects of LaJolla, C.A. 92161 Iodine Metabolism, Blackwell Scientific Publications, Oxford U.S.A. (1964), pp. 3-37
Downloaded by: University of Pennsylvania Libraries. Copyrighted material.
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