Sincalide

Sincalide is the C-terminal octapeptide of cholecystokinin, sulfated at the tyrosine residue, which is the minimum fragment retaining full biological potency. Through CCK-A (CCK1) receptors on gallbladder smooth muscle it produces vigorous contraction while simultaneously relaxing the sphincter of Oddi, expelling bile into the duodenum. On pancreatic acinar cells the same receptor drives release of an enzyme-rich secretion, which is why it complements secretin in combined pancreatic function testing. It also accelerates small bowel transit, a property occasionally used to speed barium studies. Its effects are fast and short-lived, which suits a diagnostic agent but makes it useless as a therapeutic.

Targets: CCK-A (CCK1) receptor, Gallbladder smooth muscle, Sphincter of Oddi, Pancreatic acinar cells

• · 0.02 mcg/kg — about 1.4 mcg for a 70 kg adult. The 60-minute infusion is now the preferred method because it produces far less cramping and a more reproducible ejection fraction than the old rapid bolus.
• · 0.02 mcg/kg as a bolus. Still on the label but largely abandoned for gallbladder ejection fraction because it causes marked abdominal cramping and unreliable readings.

Work out your exact syringe units →

• very commonAbdominal cramping and pain— Much more common with rapid bolus dosing; the 60-minute infusion largely solves this.
• commonNausea
• commonUrge to defecate— A direct consequence of accelerated small bowel and colonic transit.
• uncommonDizziness, flushing, sweating
• rareHypersensitivity reaction

• Intestinal obstruction — forcing motility against an obstruction is dangerous.
• Known hypersensitivity to sincalide.
• Pregnancy — the label advises against use.
• Recent opioid use produces false-positive results by contracting the sphincter of Oddi; opioids should be withheld beforehand.

• conflictopioids — Contract the sphincter of Oddi and invalidate gallbladder ejection fraction results. Withhold for at least a few half-lives before testing.
• conflictanticholinergics — Blunt gallbladder contraction and produce falsely low ejection fractions.
• synergysecretin — Used together in combined pancreatic function testing — secretin for ductal bicarbonate, sincalide for acinar enzymes.
• cautionglp-1-agonists — GLP-1 drugs slow gallbladder motility and can confound ejection fraction results; note recent use.

• · Gallbladder ejection fraction on hepatobiliary scintigraphy, with 38% commonly used as the lower limit of normal on the infusion protocol.
• · Symptom reproduction during infusion is recorded but is a poor standalone diagnostic criterion.
• · Observe briefly for hypersensitivity after administration.

FDA-approved diagnostic agent, prescription-only, hospital and imaging-centre use. Periodic supply shortages have affected availability.

• Kinevac (sincalide) US prescribing information, Bracco (label)
• SNMMI consensus recommendations on standardised sincalide cholescintigraphy, 2010 (guideline)
• Rome IV criteria for functional gallbladder disorder (guideline)

Sincalide is the business end of cholecystokinin, and its pharmacology is almost entirely explained by one structural fact: the sulfated tyrosine. CCK and gastrin share an identical C-terminal pentapeptide, Gly-Trp-Met-Asp-Phe-NH2, and therefore both bind both CCK1 and CCK2 receptors. What distinguishes them is sulfation. Sulfation of the tyrosine seven residues from the C-terminus confers roughly thousandfold selectivity for CCK1. Remove it and you have a molecule that behaves like gastrin. The IUPHAR data for CCK-8 reflect this: high potency at CCK2 (pIC50 9.9-10.0, human) and a wide spread at rat CCK1 across assays (pIC50 7.2 to 9.9). At CCK1 receptors on gallbladder smooth muscle, sincalide produces vigorous Gq-coupled contraction via phospholipase C, IP3 and intracellular calcium release. Simultaneously it relaxes the sphincter of Oddi, largely through nitrergic and VIP-ergic enteric neurons. Contract the reservoir, open the outlet — bile is expelled into the duodenum. On pancreatic acinar cells the same receptor drives release of an enzyme-rich secretion, which is the complement to secretin's bicarbonate-rich ductal secretion. The practical development that matters most for anyone actually undergoing this test is the shift from bolus to infusion. A rapid bolus produces supraphysiological receptor occupancy, violent contraction, and cramping severe enough to distort the measurement — and paradoxically a less reproducible ejection fraction, because a maximally and abruptly stimulated gallbladder does not empty in a physiologically meaningful way. The interdisciplinary consensus recommendation is 0.02 mcg/kg infused over 60 minutes, with a gallbladder ejection fraction below 38% taken as abnormal. This gives far less cramping and much tighter reproducibility. Worth flagging a genuine discrepancy: the current Kinevac label describes 0.12 mcg/kg diluted in 100 mL of saline and infused over 50 minutes at 2 mL per minute for gallbladder contraction, alongside the 0.02 mcg/kg bolus. The widely used clinical protocol from the consensus panel is 0.02 mcg/kg over 60 minutes. These are different regimens and the Core record's description matches the consensus rather than the label. If you are interpreting a report, find out which was used. The deeper problem with the test is not pharmacological. Sincalide reliably measures gallbladder contraction. Whether a low ejection fraction predicts benefit from cholecystectomy is genuinely contested, and a normal-looking number does not exclude biliary pain.

The most consequential failure is not a drug effect at all — it is that a low gallbladder ejection fraction gets treated as a surgical indication when the underlying evidence for that is genuinely contested. Sincalide reliably measures contraction. Whether contraction predicts who benefits from cholecystectomy is disputed in the literature, and there are patients who have had a gallbladder removed on the strength of a number produced by a non-standardised protocol. The second is protocol mismatch. Bolus and infusion produce different ejection fractions, and the label's 0.12 mcg/kg over 50 minutes is a different regimen again from the consensus 0.02 mcg/kg over 60 minutes. The 38% threshold belongs to the consensus infusion protocol. Applying it to a number generated by a bolus is a methodological error that happens routinely. The third is opioids. A patient on any opioid in the preceding days will have a contracted sphincter of Oddi and a suppressed ejection fraction. If the history is not taken carefully, the result is meaningless. The fourth is the cramping itself, which with bolus dosing is severe enough that patients remember it. It is also sometimes recorded as 'symptom reproduction' and used as supporting diagnostic evidence, which the consensus panel considers a poor standalone criterion. Reproducing pain by violently contracting a gallbladder does not establish that the gallbladder is the cause of spontaneous pain. The fifth is practical: the product has had recurrent supply shortages, and it is a preservative-free single-use vial reconstituted with 5 mL of sterile water and shaken for at least a minute.

1. 1.4 mcgSingle procedure — consensus protocol — 0.02 mcg/kg — about 1.4 mcg for a 70 kg adult — infused over 60 minutes during cholescintigraphy. This is the interdisciplinary consensus method and is what the 38% ejection fraction threshold is calibrated to. Far less cramping and much better reproducibility than the bolus.
2. 8.4 mcgSingle procedure — label infusion regimen — The current Kinevac label describes 0.12 mcg/kg diluted in 100 mL of 0.9% saline and infused over 50 minutes at 2 mL per minute — about 8.4 mcg for a 70 kg adult. This is a different regimen from the consensus protocol and is worth knowing about when reading a report, because the ejection fraction thresholds are not interchangeable.
3. 1.4 mcgSingle procedure — legacy bolus — 0.02 mcg/kg injected over 30 to 60 seconds. Still on the label but largely abandoned for gallbladder ejection fraction because it causes marked cramping and unreliable readings. Still used for accelerating small bowel transit in barium studies.
4. —Repeat — The label permits a repeat dose after 15 minutes if the gallbladder does not respond. Be sceptical: a non-response usually means a genuinely non-functioning gallbladder, not underdosing.

• CCK1 (CCK-A) receptor, gallbladder smooth muscle — Rat CCK1 pIC50 reported across a wide range, 7.2 to 9.9 depending on assay, per the IUPHAR/BPS Guide to Pharmacology. Human CCK1 is recorded as a full agonist interaction without a quantitative value.

  Gq-coupled contraction via phospholipase C, IP3 and calcium release. Maximal contraction 5-15 minutes after a bolus. This is the measured endpoint in cholescintigraphy.

• CCK2 (CCK-B / gastrin) receptor — Human pIC50 9.9-10.0, full agonist, per the IUPHAR/BPS Guide to Pharmacology.

  High potency here too — sincalide is not a selective CCK1 agonist in absolute terms, it simply retains CCK1 activity that desulfated CCK-8 loses. CCK2 activity contributes to gastric acid effects and, centrally, to the anxiogenic and nausea effects of CCK peptides.

• Sphincter of Oddi — Indirect, via enteric neurons.

  Relaxation, principally through nitrergic and VIP-ergic pathways. This is why opioids invalidate the test — they contract the sphincter and oppose the drug directly.

• Pancreatic acinar cells — Same CCK1 receptor.

  Release of enzyme-rich pancreatic secretion. Complements secretin's ductal bicarbonate response in combined pancreatic function testing.

• Gastrointestinal smooth muscle, small bowel and colon — Same receptor family.

  Accelerated transit. This is a labelled indication for speeding barium studies, and it is why the urge to defecate is a common effect during infusion.

• FDA approval of Kinevac (sincalide) for gallbladder contraction, stimulation of pancreatic secretion, and acceleration of small bowel transit Approved

  Approved diagnostic indications. The label documents maximal gallbladder contraction 5-15 minutes after a 0.02 mcg/kg bolus and specifies a 0.12 mcg/kg 50-minute infusion regimen for gallbladder contraction.

• Cholecystokinin-cholescintigraphy in adults: consensus recommendations of an interdisciplinary panel (DiBaise et al.) Consensus guideline · 2011

  Standardised sincalide cholescintigraphy methodology, recommending 0.02 mcg/kg infused over 60 minutes and establishing the reference ejection fraction threshold. Published in parallel in Clinical Gastroenterology and Hepatology and Clinical Nuclear Medicine.

Gallbladder contraction begins within about 5 minutes of a bolus and is maximal at 5-15 minutes, with the effect largely over by 30-60 minutes. On the 60-minute infusion protocol the contraction is gradual and the ejection fraction is calculated across the whole infusion. The plasma half-life is on the order of minutes. Everything about this drug is measured in minutes, not days.

The one legitimate pairing is with secretin, in sequence, during combined pancreatic function testing: secretin drives the ductal bicarbonate response and sincalide the acinar enzyme response. Together they characterise both compartments of exocrine pancreatic function. Everything else in this section is about what must be withheld. Opioids contract the sphincter of Oddi and produce falsely low ejection fractions — this is the classic error and it leads to unnecessary surgery. Anticholinergics blunt gallbladder contraction directly. GLP-1 receptor agonists slow gallbladder motility and, given their current prevalence, are now a frequent unrecognised confounder. Calcium channel blockers and progesterone also reduce gallbladder contractility and are worth noting on the request form. There is no therapeutic stacking concept because there is no therapeutic use.

Sincalide and secretin are the two diagnostic peptides in this class and they are complementary rather than competing: sincalide for acinar enzyme secretion and gallbladder contraction, secretin for ductal bicarbonate. Combined pancreatic function testing uses both. The useful contrast within the corpus is with the motilin agonists. Both sincalide and erythromycin accelerate gastrointestinal transit, both cause cramping as their core side effect, and both illustrate the same principle — that a drug which forces smooth muscle to contract is dose-limited by the fact that forceful contraction hurts. Sincalide gets away with it because it is administered once; erythromycin does not because it is administered repeatedly. Against a fatty meal challenge, which is the physiological alternative for stimulating gallbladder contraction, sincalide is more standardised and reproducible but less physiological. Some centres still use a fatty meal precisely because it produces a more natural stimulus. One broader point: sincalide is the peptide in this corpus with the largest gap between how well the pharmacology is understood and how contested its clinical utility is. The drug does exactly what it says. Whether the test built around it should change management is the open question.

Not applicable. A single-use hospital diagnostic billed per procedure. There is no monthly cost concept.

• ?The Kinevac label does not state half-life, clearance, volume of distribution or protein binding, and I could not verify the commonly quoted 2-3 minute half-life against a primary source. Those fields are null accordingly.
• ?There is a genuine discrepancy between the label's 0.12 mcg/kg over 50 minutes infusion regimen and the widely used consensus protocol of 0.02 mcg/kg over 60 minutes. Both are documented; the Core record describes the consensus method. Anyone interpreting a scintigraphy report needs to know which was used.
• ?The 38% ejection fraction threshold is protocol-specific and was verified only as a widely used consensus figure; it is not a label value.
• ?Human CCK1 affinity is recorded in the IUPHAR database as a qualitative full-agonist interaction without a quantitative value; only rat CCK1 has numbers, and they span nearly three log units across assays.
• ?Blood-brain barrier penetration is entered as 'partial' because CCK peptides have well-documented central effects including anxiogenesis and nausea, but I did not verify penetration of peripherally administered sincalide specifically.
• ?Whether a low gallbladder ejection fraction predicts benefit from cholecystectomy is genuinely contested in the literature and I have not resolved that debate here — I have only flagged it.

• KINEVAC (sincalide) for injection, US prescribing information Bracco Diagnostics Inc., DailyMed / FDA label

  Source for the sulfated, amidated octapeptide structure; the 5-15 minute maximal contraction after a 0.02 mcg/kg bolus; and the 0.12 mcg/kg over 50 minutes infusion regimen. Note that the label does not state half-life, clearance or volume of distribution.

• Cholecystokinin-cholescintigraphy in adults: consensus recommendations of an interdisciplinary panel DiBaise JK, Richmond BK, Ziessman HA, et al., Clinical Gastroenterology and Hepatology, 2011 · PMID 21334459

  The standardisation paper behind the 0.02 mcg/kg 60-minute infusion protocol that most centres actually use, and the source of the ejection fraction reference threshold.

• Cholecystokinin-cholescintigraphy in adults: consensus recommendations of an interdisciplinary panel DiBaise JK, Richmond BK, Ziessman HA, et al., Clinical Nuclear Medicine, 2012 · PMID 22157031

  The nuclear medicine publication of the same consensus recommendations.

• CCK-8 (sincalide), IUPHAR/BPS Guide to Pharmacology ligand 864 — CCK2 pIC50 9.9-10.0 human; CCK1 pIC50 7.2-9.9 rat IUPHAR/BPS Guide to Pharmacology

  Receptor affinity data across CCK1 and CCK2, and confirmation that sincalide is the INN for CCK-8.