Transport Characteristics of Propantheline Across Rat Intestinal Brush Border Membrane

Shinmoto, Hiroshi; Kawai, Shinji; Miyazaki, Katsumi; Arita, Takaichi

doi:10.1111/j.2042-7158.1988.tb05213.x

Cited by 21 publications

(6 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Both the lipophilicity and their charge will affect their distribution into the tissues and transport across the plasma membrane and BBB [33,34]. …”

Section: Resultsmentioning

confidence: 99%

Comprehensive pharmacokinetic studies and oral bioavailability of two Mn porphyrin-based SOD mimics, MnTE-2-PyP5+ and MnTnHex-2-PyP5+

Weitner

Kos

Sheng

et al. 2013

Free Radical Biology and Medicine

View full text Add to dashboard Cite

The cationic, ortho Mn(III) N-alkylpyridylporphyrins (alkyl=ethyl, E, and n-hexyl, nHex) MnTE-2-PyP5+ (AEOL10113, FBC-007) and MnTnHex-2-PyP5+ have proven efficacious in numerous in vivo animal models of diseases having oxidative stress in common. The remarkable therapeutic efficacy observed is due to their: (1) ability to catalytically remove normalO2•− and ONOO− and other reactive species; (2) ability to modulate redox-based signaling pathways; (3) accumulation within critical cellular compartments, i.e., mitochondria; and (4) ability to cross the blood–brain barrier. The similar redox activities of both compounds are related to the similar electronic and electrostatic environments around the metal active sites, whereas their different bioavailabilities are presumably influenced by the differences in lipophilicity, bulkiness, and shape. Both porphyrins are water soluble, but MnTnHex-2-PyP5+ is approximately 4 orders of magnitude more lipophilic than MnTE-2-PyP5+, which should positively affect its ability to pass through biological membranes, making it more efficacious in vivo at lower doses. To gain insight into the in vivo tissue distribution of Mn porphyrins and its impact upon their therapeutic efficacy and mechanistic aspects of action, as well as to provide data that would ensure proper dosing regimens, we conducted comprehensive pharmacokinetic (PK) studies for 24 h after single-dose drug administration. The porphyrins were administered intravenously (iv), intraperitoneally (ip), and via oral gavage at the following doses: 10 mg/kg MnTE-2-PyP5+ and 0.5 or 2 mg/kg MnTnHex-2-PyP5+. Drug levels in plasma and various organs (liver, kidney, spleen, heart, lung, brain) were determined and PK parameters calculated (Cmax, C24 h, tmax, and AUC). Regardless of high water solubility and pentacationic charge of these Mn porphyrins, they are orally available. The oral availability (based on plasma AUCoral/AUCiv) is 23% for MnTE-2-PyP5+ and 21% for MnTnHex-2-PyP5+. Despite the fivefold lower dose administered, the AUC values for liver, heart, and spleen are higher for MnTnHex-2-PyP5+ than for MnTE-2-PyP5+ (and comparable for other organs), clearly demonstrating the better tissue penetration and tissue retention of the more lipophilic MnTnHex-2-PyP5+.

show abstract

“…Both the lipophilicity and their charge will affect their distribution into the tissues and transport across the plasma membrane and BBB [33,34]. …”

Section: Resultsmentioning

confidence: 99%

Comprehensive pharmacokinetic studies and oral bioavailability of two Mn porphyrin-based SOD mimics, MnTE-2-PyP5+ and MnTnHex-2-PyP5+

Weitner

Kos

Sheng

et al. 2013

Free Radical Biology and Medicine

View full text Add to dashboard Cite

show abstract

“…Using rat small intestinal brush border membrane vesicles, we have shown that propantheline, a quaternary ammonium compound, is highly bound and that this binding to the membrane is the first step in the absorption process of propantheline from rat small intestine (Saitoh et al 1987). We also reported that propantheline binding to the brush border membrane was significantly inhibited by chlorpromazine, promethazine, imipramine and diphenhydramine (Saitoh et al 1988). Chlorpromazine and diphenhydramine exhibited a competitive type of inhibition.…”

mentioning

confidence: 87%

Binding of Organic Cations to Brush Border Membrane from Rat Small Intestine

Shinmoto

Kawai

Iseki

et al. 1988

Journal of Pharmacy and Pharmacology

Self Cite

View full text Add to dashboard Cite

The binding of six organic cations (chlorpromazine, promethazine, imipramine, diphenhydramine, methochlorpromazine and propantheline) to the brush border membrane isolated from rat small intestine has been investigated. The cations were bound to the membrane to varying extents, the order of binding being chlorpromazine greater than promethazine greater than methochlorpromazine greater than imipramine greater than propantheline greater than diphenhydramine. There was no relation between binding and the chloroform-water partition coefficient. Chlorpromazine binding was significantly decreased in the presence of imipramine, methochlorpromazine and propantheline. Anionic compounds (indomethacin and xanthene-9-carboxylic acid) did not affect chlorpromazine binding. High and low affinity binding of the cations to the intestinal brush border membrane was demonstrated with Scatchard plots and Hill plots. Imipramine and methochlorpromazine inhibited chlorpromazine binding at both binding sites. From the results, it was suggested that the organic cations tested were specifically bound to common binding sites on the brush border membrane.

show abstract

“…Internal factors e) Contribution of P-gp: It is possible that propantheline is a substate of P-gp, 4,5) but there is no information to show that imidafenacin is a substrate or inhibitor of Pgp.…”

Section: To the Editormentioning

confidence: 99%

Response to “Suspected Differential Interactions of Digoxin with Imidafenacin and Propantheline; Some Thoughts for Introspection”

Nakade¹,

Ohno²,

Ogawa³

2009

Drug Metabolism and Pharmacokinetics

View full text Add to dashboard Cite

We thank Dr. Srinivas for his thoughtful comments 1) in response to our paper on the influence of imidafenacin on digoxin pharmacokinetics. 2) These comments address possible causes of different effects on digoxin exerted by imidafenacin in our study and by propantheline in a previous report, with the assumption that the two anticholinergic drugs should have essentially the same effects on digoxin. 1) We categorize the factors pointed out by Srinivas as 1) external factors that depend on the study design and 2) internal factors that depend on the compound. We would like to give our opinions on these issues and add some information on solifenacin, another anticholinergic agent, in discussing the different results from imidafenacin and propantheline studies.1. External factors a) Dosage form of digoxin: Digoxin tablets, more susceptible to interaction than digoxin capsules, were used in our study and there is no concern about the dosage form. b) Dose of digoxin: the dose of digoxin in our study was less than that of propantheline. Half the clinical dose of digoxin was used to ensure the safety of the subjects. c) Production batch of digoxin tablets: there is difference in batches between the imidafenacin and propantheline studies. d) Measurement of digoxin: Generally, digoxin is measured by radioimmunoassay (RIA). However, the low sensitivity of RIA is a concern and thus we have established a digoxin assay using LC/MS/MS with higher sensitivity 3) and generally higher specificity compared to RIA.2. Internal factors e) Contribution of P-gp: It is possible that propantheline is a substate of P-gp, 4,5) but there is no information to show that imidafenacin is a substrate or inhibitor of Pgp.f) Metabolism in the small intestine: CYP3A4 metabolism in the small intestine does not seem to have much relevance to this issue; imidafenacin is not metabolized in human small intestinal microsomes. 6) g) Selectivity for muscarinic receptors: As we indicated in a previous paper, propantheline has no selectivity for the muscarinic receptor subtypes M1, M2 and M3, 7) whereas imidafenacin is an M1 and M3 dual antagonist with low affinity for the M2 subtype. 8) However, the physiological roles of these receptor subtypes have not been completely elucidated.We would like to add that solifenacin, an anticholinergic drug used for overactive bladder treatment, has almost no affect on digoxin bioavilability, 9) as with imidafenacin. The digoxin dose in the solifenacin study was the same as in the imidafenacin study and the selectivity of solifenacin for muscarinic receptor subtypes is similar to that of imidafenacin. 10) Too, solifenacin is a weak inhibitor of P-gp. 11) Based on our findings, differences in the digoxin dose and selectivity for muscarinic receptor subtypes remain factors that may account for the different effects on digoxin observed for imidafenacin (and solifenacin) compared to propantheline. However, other factors may complicate these effects and it is difficult to identify the exact causes. Nevertheless, the results from...

show abstract

Transport Characteristics of Propantheline Across Rat Intestinal Brush Border Membrane

Cited by 21 publications

References 20 publications

Comprehensive pharmacokinetic studies and oral bioavailability of two Mn porphyrin-based SOD mimics, MnTE-2-PyP5+ and MnTnHex-2-PyP5+

Comprehensive pharmacokinetic studies and oral bioavailability of two Mn porphyrin-based SOD mimics, MnTE-2-PyP5+ and MnTnHex-2-PyP5+

Binding of Organic Cations to Brush Border Membrane from Rat Small Intestine

Response to “Suspected Differential Interactions of Digoxin with Imidafenacin and Propantheline; Some Thoughts for Introspection”

Contact Info

Product

Resources

About