Loperamide in rat intestines: A unique disposition

Miyazaki, Hisashi; Nambu, Keiko; Hashimoto, Masahisa

doi:10.1016/0024-3205(82)90294-6

Cited by 13 publications

(6 citation statements)

References 9 publications

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“…Apart from this opioid-specific antisecretory action, non-opioid action components of loperamide have been suggested, i.e., calcium channel blocking-like properties (Burleigh, 1988) and inhibition of calmodulin at micromolar concentrations (Stoll et al, 1988). However, irrespective of the particular mechanisms of the antisecretory/antidiarrhoeal action of loperamide, its predominant peripheral action has been attributed to its unique pharmacokinetic disposition (Miyazaki et al, 1982). This may be due to enterohepatic shunting (see Awouters et al, 1983;Ooms et al, 1984) and accumulation of loperamide within the intestinal wall possibly caused by its surface tension-lowering properties (Wiister & Herz, 1978).…”

Section: Introductionmentioning

confidence: 99%

Unexpected prosecretory action component of loperamide at μ–opioid receptors in the guinea‐pig colonic mucosa in vitro

Kromer

1995

British J Pharmacology

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Section: Introductionmentioning

confidence: 99%

Unexpected prosecretory action component of loperamide at μ–opioid receptors in the guinea‐pig colonic mucosa in vitro

Kromer

1995

British J Pharmacology

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“…Although LOP can bind to either peripheral or brain MORs, orally administered LOP is almost entirely retained in the intestinal epithelium and lumen ( Miller et al, 2017 ; Miyazaki et al, 1982 ; Miyazaki et al, 1979 ; Vakkalanka et al, 2017 ). Thus, with a therapeutic dose of 2–4 mg, plasma levels of LOP in humans generally do not exceed 2 ng/ml (∼4 nM), suggesting that relatively little paracellular transport of LOP occurs.…”

Section: Discussionmentioning

confidence: 99%

“…LOP is a medication that is widely used to treat diarrhea and is known to act through a mechanism involving activation of enteric μ-opioid receptors (MORs) leading to slowed intestinal motility ( Mackerer et al, 1976 ; Otterson and Sarna, 1994 ). At therapeutic doses (2–4 mg), LOP is largely retained in the intestinal lumen and epithelium, with very low absorption into the bloodstream and central nervous system; thus, the medicinal actions of LOP are limited to the gastrointestinal tract ( Miller et al, 2017 ; Miyazaki et al, 1982 ; Miyazaki et al, 1979 ; Sadeque et al, 2000 ). Aside from activation of opioid receptors, LOP is also known to affect ion permeabilities in epithelial cells ( Wehner et al, 1989 ), although mechanisms underlying these effects have been unclear.…”

Section: Introductionmentioning

confidence: 99%

State-dependent inhibition of BK channels by the opioid agonist loperamide

Vouga

Rockman

Yan

et al. 2021

Journal of General Physiology

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Large-conductance Ca2+-activated K+ (BK) channels control a range of physiological functions, and their dysfunction is linked to human disease. We have found that the widely used drug loperamide (LOP) can inhibit activity of BK channels composed of either α-subunits (BKα channels) or α-subunits plus the auxiliary γ1-subunit (BKα/γ1 channels), and here we analyze the molecular mechanism of LOP action. LOP applied at the cytosolic side of the membrane rapidly and reversibly inhibited BK current, an effect that appeared as a decay in voltage-activated BK currents. The apparent affinity for LOP decreased with hyperpolarization in a manner consistent with LOP behaving as an inhibitor of open, activated channels. Increasing LOP concentration reduced the half-maximal activation voltage, consistent with relative stabilization of the LOP-inhibited open state. Single-channel recordings revealed that LOP did not reduce unitary BK channel current, but instead decreased BK channel open probability and mean open times. LOP elicited use-dependent inhibition, in which trains of brief depolarizing steps lead to accumulated reduction of BK current, whereas single brief depolarizing steps do not. The principal effects of LOP on BK channel gating are described by a mechanism in which LOP acts as a state-dependent pore blocker. Our results suggest that therapeutic doses of LOP may act in part by inhibiting K+ efflux through intestinal BK channels.

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“…We do not know of data pertaining to intestinal luminal loperamide con-centrations after oral administration. However, it has been reported that in-vitro transepithelial intestinal transport of loperamide is poor, and that the drug is likely to accumulate in the intestinal mucosa (Miyazaki et al 1982;Brayden et al 1997). Thus, it could be possible that an oral intake of 4 mg (8 mmol) loperamide, a recommended initial dose to treat traveller's diarrhoea, or higher doses to treat short bowel syndromes may generate suf®ciently high luminal concentrations to inhibit absorptive processes.…”

Section: Treatmentmentioning

confidence: 99%

Effect of Loperamide on Na+/d-Glucose Cotransporter Activity in Mouse Small Intestine

Klaren

Giesberts

Chapman

et al. 2000

Journal of Pharmacy and Pharmacology

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The mu-opioid agonist loperamide is an antidiarrhoeal drug which inhibits intestinal motility and secretion. Its anti-absorptive effects are less well investigated, but may be mediated through calmodulin. We have investigated further the effect of loperamide on the intestinal Na+-dependent D-glucose transporter (SGLT1). Brush-border membrane vesicles were prepared from mouse small intestine, and uptake of [3H]glucose was measured. Na+-dependent glucose uptake displayed the typical overshoot at 34 s; the peak value was 1.6 nmol mg(-1). The overshoot disappeared in the presence of phlorizin or when Na+ was replaced by K+. Extravesicular loperamide dose-dependently inhibited SGLT1 activity with an IC50 value of 450 micromol L(-1). Loperamide displayed a mixed inhibition type: the apparent Vmax decreased from 0.9 to 0.5 nmol mg(-1)/15 s, the apparent Km increased from 0.23 to 1.13 mmol L(-1) glucose. Na+ kinetics were more complex, but loperamide inhibited net glucose uptake by 90% at 100 mmol L(-1) Na+. Glucose uptake was unchanged by agents affecting calmodulin activity. Loperamide inhibited intestinal Na+, K+-ATPase activity, whilst sucrase activity was unaffected. SGLT1 activity was inhibited by loperamide, but this effect was not mediated through calmodulin. As this action is only evident at high concentrations of loperamide a nonspecific mechanism may be involved.

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Loperamide in rat intestines: A unique disposition

Cited by 13 publications

References 9 publications

Unexpected prosecretory action component of loperamide at μ–opioid receptors in the guinea‐pig colonic mucosa in vitro

Unexpected prosecretory action component of loperamide at μ–opioid receptors in the guinea‐pig colonic mucosa in vitro

State-dependent inhibition of BK channels by the opioid agonist loperamide

Effect of Loperamide on Na+/d-Glucose Cotransporter Activity in Mouse Small Intestine

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