Influence of asimadoline, a new κ‐opioid receptor agonist, on tubular water absorption and vasopressin secretion in man
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Aims The purpose of the study was to investigate the effects of asimadoline, a new κ‐opioid agonist, on renal function and on hormones related to body fluid balance as well as its tolerability in healthy subjects. Methods In a placebo‐controlled, randomised, double‐blind crossover design we studied the effects of single oral doses of 1, 5, and 10 mg of asimadoline, in 24 healthy volunteers. Two hour control urine collections were followed by 2 h postdose urine collections and subsequently 2.5% saline was given i.v. at a rate of 0.3 ml min−1 kg−1 during another 2 h urine collection. Blood was obtained hourly. Arginine‐vasopressin (AVP), atrial natriuretic peptide (α‐hANP), endothelin (ET‐1) and cAMP were determined by r.i.a. or ELISA. Results GC‐MS measurements revealed Cmax values of asimadoline in plasma ranging from 18 ng ml−1 at the 1 mg dose, 91 ng ml−1 at the 5 mg dose, to 214 ng ml−1 at the 10 mg dose after an average of 1.1–1.4 h. Without effects on blood pressure, heart rate, GFR or urine electrolyte excretion, urine volume increased after 1–2 h after administration of 5 and 10 mg asimadoline from 3.3 ± 1.3 to 5.6 ± 1.4 (P < 0.05) and from 3.2 ± 1.6 to 5.5 ± 2.2 ml min−1 (P < 0.01), respectively. C H2O rose from 0.2 ± 1.5 to 2.0 ± 1.6 (P < 0.05) and from 0.6 ± 1.6 to 3.0 ± 1.6 ml min−1 (P < 0.01). Urinary excretion of AVP was suppressed only with the 10 mg dose from 46 ± 23 to 25 ± 15 fmol min−1 (P < 0.05) without and from 410 ± 206 to 181 ± 125 fmol min−1 (P < 0.05) with stimulation by 2.5% saline. Plasma AVP was suppressed only by the 10 mg dose of asimadoline in six of eight subjects during the 2.5% saline infusion. Changes in the α‐hANP or ET‐1 systems were not affected by asimadoline. Conclusions Asimadoline is diuretic in man after single doses of 5 or 10 mg probably through a direct effect at the renal tubular level. Suppression of AVP secretion was observed only at the highest dose level of 10 mg of asimadoline.
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Acute administration of the kappa-opioid receptor agonist asimadoline in normal subjects at doses 1, 5, and 10 mg reduced plasma AVP during 2.5% saline infusion in 6 of 8 participants receiving the highest dose of 10 mg, compared to placebo.
“It has also been shown that acute administration of the kappa-opioid receptor agonist asimadoline in normal subjects at doses 1, 5, and 10 mg reduced plasma AVP during 2.5% saline infusion in 6 of 8 participants receiving the highest dose of 10 mg, compared to placebo (180).”
From Exogenous Opioids and the Human Endocrine System: An Endocrine Society Scientific Statement (2024) · cites this paper as [180]
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- Authors
- Kramer, H. J., Uhl, W., Ladstetter, B., & Bäcker, A.
- Affiliations
- University of Bonn (DE)
- Merck KGaA, Darmstadt (Germany) (DE)
- Corresponding author
- Kramer, H. J.
- Venue
- British Journal of Clinical Pharmacology
- Publisher
- Wiley
- Published
- 2000-09
- Volume
- 50
- Issue
- 3
- Pages
- 227-235
- ISSN
- 0306-5251 (ISSN-L)
- 1365-2125
- PMC
- PMC2014989
- OpenAlex
- W1527092281
- Semantic Scholar
- bf827235842f46e6a9eb1eef18e647c736622535
- Cited by
- 32
- References
- 32
- Citations by year
- 2026: 1 · 2024: 2 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 1 · 2014: 2 · 2012: 1
- FWCI
- 0.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- British Journal of Clinical Pharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Electrolyte and hormonal disorders
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Keywords
- kappa opioid receptor agonists, vasopressin release, vasopressin, atrial natriuretic peptide, endothelin-1, cyclic AMP, urine output, fluid balance, renal function, drug tolerability, plasma pharmacokinetics, healthy volunteers, dose-dependent effects, water diuresis
- MeSH terms
- Acetamides, Cyclic AMP, Adult, Analgesics, Opioid, Double-Blind Method, Humans, Kidney Function Tests, Kidney Tubules, Male, Atrial Natriuretic Factor, Pyrrolidines, Vasopressins, Receptors, Opioid, kappa, Cross-Over Studies, Endothelin-1
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