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Home , Somatostatin, Somatostatin family

Gut 1994; supplement 3: S 1-S4 Si and somatostatin analogues: effects pharmacokinetics and pharmacodynamic Gut: first published as 10.1136/gut.35.3_Suppl.S1 on 1 January 1994. Downloaded from

A G Harris

Abstract (amylase, trypsin, lipase). Somatostatin is a 14 increases intestinal transit time and that inhibits pancreatic exocrine and decreases endogenous fluid secretion in endocrine secretion. Its clinical applica- the jejunum and , thus increasing tion has been limited by its very short half the absorption of water and electrolytes. life, necessitating continuous intravenous These pharmacological effects of the infusion. Octreotide is an 8 amino acid analogue point to its therapeutic role in a synthetic analogue of somatostatin that variety of endocrine and gastrointestinal possesses similar pharmacological effects. disorders. It has a much longer duration of action, (Gut 1994; supplement 3: SI -S4) however, and can be given subcuta- neously. Both the intravenous and sub- cutaneous routes ofinjection of octreotide The are well tolerated. Peak serum concentra- tions occur within 30 minutes after NATIVE MOLECULAR STRUCTURES subcutaneous administration and within Somatostatin is the name given to a family of four minutes of a three minute intra- , the original member of which, venous infusion. Serum concentration somatostatin 14, a tetradecapeptide, was first increases linearly with dose. Octreotide is isolated from ovine hypothalami by Roger distributed rapidly, mainly in the plasma, Guillemin's group at the Salk Institute, in the where it is 65% protein bound. The course of an unsuccessful search for growth elimination half life is about 1.5 hours releasing factor. The molecule was and about 32% of a subcutaneous dose shown to inhibit release from is excreted in the urine as unchanged cultured pituitary cells, and for a while was octreotide. Octreotide inhibits gastro- known variously as growth hormone release enteropancreatic secretion, especially of inhibiting factor, somatotropin release inhibi- ting factor, and growth hormone release

, , , http://gut.bmj.com/ gastric inhibitory polypeptide, and inhibiting factor, until somatostatin - proposed . It also inhibits both release of by the Salk group in a note to the original stimulating hormone and article - emerged as standard. growth hormone secretion in response to The native molecule was found to have a Division Clinical exercise, insulin induced hypoglycaemia, cyclic structure joined by two intramolecular Pharmacology, and argenine stimulation. Octreotide disulphide bonds between the two cysteine Department of

reduces splanchnic blood flow in healthy residues (Figure). The linear reduced on September 24, 2021 by guest. Protected copyright. Medicine, Cedars- Sinai Medical Center, volunteers and hepatic venous pressure in sequence, however, proved to have the same Los Angeles, cirrhotic patients. It can accelerate or biological activity as the cyclic form in vitro - California, USA delay gastric emptying, prolong transit that is, the cyclic form was not essential for A G Harris time at moderate to high doses, stimulate recognition by specific somatostatin receptors. Correspondence to: motility at low doses, and inhibit gall A second native form of somatostatin was Dr A G Harris, Division Clinical Pharmacology, bladder emptying. Octreotide consider- reported in 1980.2 Somatostatin 28 contains Department of Medicine, ably inhibits pentagastrin stimulated the amino acid sequence of somatostatin 14, Cedars-Sinai Medical Center, Los Angeles, secretion and significantly extended by 14 residues at the N-terminus. California, USA. diminishes exocrine pancreatic function Though there is some evidence that somato- statin 28 may act as a precursor, it also operates as a hormone in its own right, with Human somatostatin Octreotide a slightly different spectrum of activity in different tissues. Thus somatostatin 28 suppresses growth hormone for much longer, but is less effective in suppressing gastric acid. There is virtually no somatostatin 28 in the and . It has been shown, however, to be the dominant form lower down the gut.3 4

LOCALISATION Large amounts of somatostatin are found in Amino acids essential the gastrointestinal system, including the -4 for receptor binding , visceral autonomic nervous system, Amino acid composition ofsomatostatin and octreotide. endocrine cells, and gut lumen. Immuno- S2 Harmis

cytochemical studies show that somatostatin is independent mechanisms29 30 and may act by localised to the D cells of the pancreas and gut affecting calcium transport through the cell mucosa, particularly in the gastric fundus, membrane.3' Because somatostatin inhibits

antrum, and duodenum.5 6D cells are situated many aspects of cellular function, including Gut: first published as 10.1136/gut.35.3_Suppl.S1 on 1 January 1994. Downloaded from in the lower third of the crypts, from where endocrine secretion, muscular contraction, they extend cytoplasmic processes along the and cellular growth, it must antagonise a basal membranes to the basal pole of variety of intracellular signalling programmes. neighbouring glands.7 Thus somatostatin is The dephosphorylation processes crucial for well placed to exercise paracrine control of secretory activity intimately participate in other endocrine cells in the gut, for example, inhibition by somatostatin at the molecular those responsible for the synthesis and release level. After binding to its receptor, somato- of gastrin. The D cells also have microvilli in statin probably acts as a dephosphorylator to direct contact with the lumen, thus providing a inhibit secretory processes, but whether the pathway by which changes in gut content can hormone also interacts with DNA to affect influence somatostatin production, either into transcription is disputed. the lumen or into the circulation. In addition, Because of its many diverse physiological the gut is innervated by extrinsic and intrinsic effects, native somatostatin has been investi- somatostatin containing neurones, with the gated for the treatment of and gut intrinsic neurones being present in both the endocrine tumours. Despite its many potential submucosal and myenteric plexuses. uses, however, the clinical applications of somatostatin were limited by a very short half life of two to three minutes, necessitating con- ACTIONS tinuous intravenous infusion and resulting in These anatomical considerations explain how rebound hypersecretion of after somatostatin can have multiple endocrine, infusion. paracrine, and exocrine functions, in addition to its central growth hormone release inhibit- ing effect. The first description of its gastro- OCTREOTIDE intestinal action was published within a year of Octreotide (Sandostatin) is an 8 amino acid the original paper.8 Somatostatin has long synthetic peptide analogue engineered to recognised inhibitory effects on pancreatic overcome the limitations of native somato- endocrine and exocrine secretion - that is, on statin.32 Octreotide retains the Phe-Trp-Lys- insulin, glucagon, and pancreatic polypep- Thr portion of the native molecule (with the tide9 10 and also on pancreatic enzyme and tryptophan residue in the D configuration), bicarbonate responses to and which is believed to constitute the essential ,l-13 recently reviewed by Layer et al. 14 pharmacophore22 23 and to be critical for gut It also inhibits the secretion of a wide variety of specificity.33 Octreotide has greater

pharmaco- http://gut.bmj.com/ stimulatory gastrointestinal hormones,'5 and logical activity than the native molecule (being decreases gastrointestinal motility and blood at least 20 times more potent in suppressing flow.118 growth hormone secretion in vivo), is more selective for the inhibition of growth hormone than of insulin, and has a much enhanced STRUCTURE-FUNCTION RELATIONS duration of action (an elimination half life of The action of native somatostatin is brief and 113 minutes compared with the to two three on September 24, 2021 by guest. Protected copyright. rapid, and is followed by rebound secretion, all minutes of somatostatin).32 The synthetic of which suggests that it inhibits release rather molecule is sufficiently stable even to retain than synthesis, perhaps by depressing exocyto- some activity on oral administration, the oral sis. 19 dose required to inhibit growth hormone secre- Somatostatin receptors have been identified tion by 50% being 125 ,ug/kg after one hour.34 in the exocrine pancreas, on islet cells secreting As octreotide is incompletely absorbed insulin, glucagon and somatostatin,20 and on after oral administration, investigation of its gastric cells.2' Binding of somatostatin to its pharmacokinetic profile used intravenous and receptor is accounted for primarily by the 4 subcutaneous injection. Both routes of injec- amino acids in positions 7 to 10.22 23 In the late tion are well tolerated and the incidence of side 1970s analogues were synthesised that were effects is low. Moreover, bioavailability is more specific in some respects than the native similar by both routes of administration. Peak peptide, for example, more effective in inhibit- serum concentrations occur within 30 minutes ing insulin than glucagon, and vice versa,24 25 after subcutaneous administration and within while the structural requirements for gastrin four minutes after a short (three minutes) inhibition seemed to differ from those required intravenous infusion. Serum concentration of for action in the pituitary. It was found that octreotide increases linearly with increasing duration of action, an important consideration doses, irrespective of whether the drug is given for pharmacological investigation and thera- subcutaneously or intravenously. The average peutic application, could be increased by sub- bioavailability of a subcutaneous dose is 1 00% stituting L-tryptophan for D-tryptophan in or greater. Distribution is rapid. After a short position 8. Preliminary results from human (three minutes) intravenous infusion, a very and animal studies with several different rapid distribution phase (tI/2b 0 142-0-210 h) analogues were reported.2628 is seen. Once in the blood, octreotide is dis- Intracellularly, somatostatin achieves its tributed mainly in the plasma where it is 65% effects by cyclic AMP dependent and protein bound - mostly to lipoproteins, and to Somatostatin and somatostatin analogues: pharmacokinetics and pharmacodynamic effects S3

a lesser degree to albumin. The elimination Postprandial hyperglycaemia and an increase half life (tl/2b) of octreotide by either route of in fasting plasma glucose have been noted, administration is approximately 1-5 hours- 30 both probably associated with the decrease in times longer than that of somatostatin. About insulin secretion. Gut: first published as 10.1136/gut.35.3_Suppl.S1 on 1 January 1994. Downloaded from 32% of a subcutaneous dose is excreted in the Effective suppression of plasma concentra- urine as unchanged octreotide. tions of insulin and glucagon has been achieved In patients with severe renal impairment, the with subcutaneous administration of doses as plasma clearance of octreotide is reduced by low as 5 ,ug given 30 minutes before a test 50%.35 This significant reduction points to the meal. Studies have shown that octreotide presence of a renal component in the elimina- induces postprandial hyperglycaemia in normal tion of the drug. Thus, when treating patients subjects.4445 Patients with non-insulin depend- with renal impairment, the dose of octreotide ent diabetes mellitus, however, do not experi- should be carefully titrated. ence deterioration in glucose tolerance.44 Other notable findings reported in the Octreotide seems to be a strong inhibitor original paper32 were that despite being much (80% decrease in healthy subjects) of secretin/ more potent than the native molecule, cholecystokinin induced pancreatic enzyme octreotide was better tolerated by laboratory secretion (amylase, trypsin, lipase) and gall animals, while preliminary trials in humans bladder contraction.46 This inhibitory effect, failed to identify any adverse effects up to the however, decreases with time. highest infused dose of 50 ,ug/hour (many Octreotide has been shown to reduce times higher than the minimal effective dose splanchnic blood flow in healthy volunteers for inhibiting arginine stimulated growth and hepatic venous pressure in cirrhotic hormone release). The safety of octreotide was patients. It has also been shown to accelerate subsequently confirmed in a wide variety or delay gastric emptying, prolong transit time of clinical situations, particularly in two at moderate to high doses, stimulate motility at unexpected respects: firstly, most studies low doses, and inhibit gall bladder emptying. reporting the use of octreotide in infants have Octreotide considerably increases intestinal shown no inhibition of growth,3$' while transit time and endogenous fluid secretion in secondly, in contrast with the native molecule, the jejunum and ileum. As a result, absorption rebound endocrine hypersecretion does not of water and electrolytes is increased. occur when octreotide is withdrawn.42 Octreotide considerably inhibits pentagas- Octreotide inhibits normal growth hormone trin stimulated gastric acid secretion47 and secretion in response to exercise, insulin significantly diminishes exocrine pancreatic induced hypoglycaemia, and arginine stimula- function (amylase, trypsin, lipase). tion. Studies have shown that octreotide Because of these diverse pharmacological inhibits the release of thyroid stimulating effects, octreotide has been studied in a wide

hormone by thyrotropin releasing hormone in variety of endocrine and gastrointestinal dis- http://gut.bmj.com/ healthy subjects. In both studies, the response orders (fistulae, variceal bleeding, diarrhoea, of to thyrotropin releasing hormone pancreatitis). was not affected. Moreover, basal thyroid 1 Brazeau P, Vale W, Burgus R, et al. Hypothalamic polypep- stimulating hormone concentration was un- tide that inhibits the secretion ofimmunoreactive pituitary affected in the absence of a thyrotropin releas- growth hormone. Science 1973; 178: 77-9. 2 Praydayrol L, Jomvall H, Mutt V, Ribet A. N-terminally ing hormone challenge. Octreotide blunts the extended somatostatin: the primary structure of somato-

luteinising hormone response to luteinising statin-28. FEBS Lett 1980; 109: 55-8. on September 24, 2021 by guest. Protected copyright. 3 Descos F, de Parscau L, Olive C, Chayvialle JA. hormone releasing hormone, but has no Somatostatin-like immunoreactivity in human gastro- effect on the response of follicle stimulating intestinal mucosa [Abstract]. 2nd International Symposium on Somatostatin, Athens, 1-3 June 1981. hormone. Adrenocorticotrophic hormone and 4 Penman E, Wass JAH, Butler MG, et al. Distribution and concentrations do not change. characterisation of immunoreactive somatostatin in human . Regul Pept 1983; 7: 53-65. Octreotide exerts a number of pharmaco- 5 Polak JM, Pearse AGE, Grimelius L, et al. Growth hormone logical effects on the gastrointestinal tract. It release inhibiting hormone in gastrointestinal and pancreatic D cells. Lancet 1975; i: 1220-2. considerably increases intestinal transit time 6 Dubois MP. Immunoreactive somatostatin is present in and endogenous fluid secretion in the jejunum discrete cells ofthe endocrine pancreas. Proc NatlAcad Sci USA 1975; 72: 1340-3. and ileum. As a result, absorption of water and 7 Larsson LI, Goltermann N, De Magistris L, et al. electrolytes is increased. Somatostatin cell processes as pathway for paracrine secretion. Science 1979; 205: 1393-5. Delay of intestinal transit time was shown in 8 Bloom SR, Mortimer CH, Thomer MG, et al. Inhibition of normal subjects undergoing steady state perfu- gastrin and gastric acid secretion by growth hormone release-inhibiting hormone. Lancet 1974; ii: 1106-9. sion studies of the small bowel. Mean transit 9 Adrian TE, Bloom SR, Besterman HS, Bryant MG. time through a 30 cm segment of jejunum PP-physiology and pathology. In: Bloom SR, ed. Gut hormones. New York: Churchill Livingstone, 1978: 254-60. was found to be increased from 4 0 to 17-0 10 Floyd JC, Fajans SS, Pek S. Physiological regulation of minutes. Additionally, a significant decrease in plasma levels of PP in man. In: Bloom SR, ed. Gut hormones. New York: Churchill Livingstone, 1978: endogenous flow from above the test segment 247-53. was noted during the treatment period.43 11 Boden G, Sivitz MC, Owen OE, et al. Somatostatin suppresses secretin and pancreatic exocrine secretion. Octreotide appreciably suppresses gastro- Science 1975; 190: 163-4. enteropancreatic secretion, especially that of 12 Dollinger HC, Raptis S, Pfeiffer EF. Effects of somatostatin on exocrine and endocrine pancreatic function stimulated insulin, glucagon, pancreatic polypeptide, by intestinal hormones in man. Horm Metab Res 1976; 8: gastric inhibitory polypeptide, and gastrin. 74-8. 13 Konturek SJ, Tasler J, Obtulowicz W, et al. Effect of growth This action has been seen both before and after hormone release inhibiting tissue on hormones stimulating meals, but is less pronounced three hours after exocrine pancreatic secretion. Jf Clin Invest 1976; 58: 1-6. 14 Layer P, vd Ohe M, Muller MK, Beglinger C. Effects of a meal, when physiological release of the somatostatin on the exocrine pancreas. Scand Jf peptides had already been completed. Gastroenterol 1991; 26: 129-36. S4 Hamris

15 Arnold R, Linkisch BG. Somatostatin and the gastro- 34 Williams G, Burrin JM, Ball JA, Joplin GF, Bloom SR. intestinal tract. Clin Gastroenterol 1980; 9: 733-53. Effective and lasting growth-hormone suppression in 16 Bloom SR, Ralphs DN, Besser GM, et al. Effect of somato- active acromegaly with oral administration of somato- statin on levels and gastric emptying [Abstract]. statin analogue SMS 201-995. Lancet 1986; ii: 774-8. Gut 1975; 16: 834. 35 Kallivretakis N, Yetis A, Del Pozo E, et al. 17 Wahren J, Felig P. Influence of somatostatin on carbo- Pharmacokinetics of SMS 201-995 in normal subjects Gut: first published as 10.1136/gut.35.3_Suppl.S1 on 1 January 1994. Downloaded from hydrate disposal and absorption in diabetes mellitus. and in patients with severe renal failure. Neuroendocrinol Lancet 1976; ii: 1213-5. Lett 1985; 7: 92. 18 Konturek SJ, Krol R, Pawlik W, et al. Pharmacology of 36 Jackson JA, Hahn HB Jr, Oltorf CE, O'Dorisio TM, Vinik somatostatin. In: Bloom SR, ed. 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