Carrier-mediated hepatic uptake of the cationic cyclopeptide, octreotide, in rats. Comparison between in vivo and in vitro.

The plasma concentration and biliary excretion profiles of a cationic cyclic octapeptide, octreotide, were compared between control rats and rats given an intravenous infusion of a bile acid, taurocholate (TCA), and an organic anion, dibromosulfophthalein (DBSP). Both TCA and DBSP reduced the plasma elimination and biliary excretion of octreotide after its intravenous bolus administration. Two mechanisms accounting for this phenomenon were considered a priori: decreased hepatic uptake from blood to liver and decreased biliary excretion from liver to bile. The tissue uptake clearance (CLup) of octreotide in plasma and several tissues was determined, and extensive uptake of octreotide (0.20 ml/min/g liver) was observed only in liver. The kinetic analysis indicated that CLup in liver fell to 10% of controls after administration of both TCA and DBSP. To compare CLup between in vivo and in vitro, the initial velocity of octreotide uptake by isolated hepatocytes and primary cultured hepatocytes was measured. The estimated kinetic parameters KM and Vmax were approximately 100 microM and 200 pmol/min/10(6) cells in both systems, respectively. Hepatic uptake clearance estimated from the in vitro data was comparable with that observed in vivo. Biliary excretion of octreotide is reduced in Eisai hyperbilirubinemic rats (EHBRs), which have a heredity defect of multispecific organic anion transporter on the bile canalicular membrane, compared with that of Sprague-Dawley rats. The kinetic analysis demonstrated that the hepatic uptake was reduced in EHBRs. The uptake study using primary cultured hepatocytes suggested that a high level of unidentified endogenous substrate(s) in EHBR plasma may be responsible for the reduction of hepatic uptake of octreotide in EHBRs. In conclusion, we have demonstrated in vivo that carrier-mediated hepatic uptake of octreotide is inhibited by TCA and DBSP and that the CLup obtained in vivo is comparable with the CLup obtained in vitro in isolated hepatocytes and primary cultured hepatocytes.

Calcium reverses octreotide inhibition of insulin and glucagon levels in patients with insulinoma and glucagonoma.

Excessive secretion of peptides causes the clinical syndromes associated with functional gastro-intestinal tumours. The somatostatin analogue octreotide acetate inhibits peptide release from a variety of tumours. This study investigated the interactions of calcium and somatostatin analogues on peptide release in two patients, one with a glucagonoma (patient A) and one with an insulinoma (patient B). Peptide responses were evaluated before (fasting levels) and after provocative tests (a 4-hour calcium infusion, an intravenous tolbutamide infusion, a secretin bolus and a standard test meal) in the absence and presence of octreotide acetate treatment (100 micrograms subcutaneously every 8 h). Patients A and B had elevated fasting plasma levels of glucagon and insulin, respectively, which were reduced by octreotide therapy by 73 and 50%, respectively. The peak provoked levels and calculated values for peptide synthesis were lower after octreotide therapy. In both patients, tolbutamide provoked most peptide release, and calcium infusion was the least susceptible to the effects of octreotide therapy. Calcium appears to inhibit octreotide suppression of glucagon and insulin secretion in patients with glucagonoma and insulinoma, respectively. Calcium may stimulate peptide release from endocrine tumours by suppressing the inhibitory effects of endogenous somatostatin. Normalisation of serum calcium, either surgically or pharmacologically, may improve the effectiveness of somatostatin analogue therapy.

Barrel rotation in rats induced by SMS 201-995: suppression by ceruletide.

Intracerebroventricular administration of SMS 201-995 (5 micrograms/rat), a somatostatin analogue, induced barrel rotation in rats. Pretreatment with ceruletide (40 micrograms/100 g b. wt., IP) 3 days or 7 days prior to the injection of SMS 201-995 significantly inhibited the response rate of barrel rotation induced by SMS 201-995, but not that induced by arginine-vasopressin (1 microgram/rat, ICV). The suppressive effect of ceruletide on barrel rotation could be partially countered by MK-329, a selective peripheral CCK (CCK-A) receptor antagonist. Desulfated cerulein did not affect the barrel rotation induced by SMS 201-995. These findings suggest that ceruletide specifically suppresses the barrel rotation evoked by SMS 201-995 in a long-lasting manner possibly acting through CCK-A receptor.

Neurobehavioral effects of intrathecal somatostatinergic treatment in subhuman primates.

We infused somatostatin and its long-acting analogue (SMS 201-995) into the intracranial subarachnoid space of eight monkeys. Chronic infusions of SMS 201-995 produced marked neurotoxic effects characterized by truncal ataxia, dysmetria, and severe bradykinesia, with normal level of consciousness. Subcutaneous injection of apomorphine, a dopaminergic agonist, promptly reversed these effects. Further studies are required before intrathecal somatostatin replacement therapy can be offered to patients with Alzheimer's disease.

Somatostatin and SMS 201-995 reverse the impairment of cognitive functions induced by cysteamine depletion of brain somatostatin.

The involvement of somatostatin in the organization of cognitive functions was studied. We assessed changes in learning and memory processes by studying the effects of cysteamine, a compound that decreases somatostatin-like immunoreactivity in the brain, somatostatin and the potent somatostatin analogue, SMS 201-995, on active avoidance behaviour, assessed with a shuttle box apparatus, or on passive avoidance behaviour. Cysteamine induced a loss of the conditioned active avoidance response acquired after 3 weeks of daily trials. The effect was observed 2 h (-29%) and 4 h (-51%) after cysteamine treatment (300 mg/kg s.c.) and disappeared after 24 h. Intracerebroventricular administration of somatostatin or SMS 201-995 to cysteamine-treated rats significantly reversed the cysteamine effects on the conditioned avoidance responses. Similar results were obtained on passive avoidance behaviour. We also investigated the effect of cysteamine treatment on brain somatostatin-sensitive adenylate cyclase. We observed that adenylate cyclase activity in the frontal cortex of cysteamine-pretreated animals was more sensitive to inhibition by the SRIF analogue, SMS 201-995, than it was in control animals. This effect was observed at concentrations of SMS 201-995 that were ineffective in control tissue. These results show that disruption of somatostatinergic transmission affects cognitive functions of rats.