Pharmacokinetics, Toxicity, Side Effects, Receptor Affinities and in vitro Radiosensitizing Effects of the Novel Metoclopramide Formulations, Sensamide and Neu‐Sensamide

Abstract

Abstract:Metoclopramide is a drug which has experienced worldwide use in the clinic for over 30 years as an antiemetic. Recently, it has also been shown to possess radio-and chemosensitizing properties in both animal tumour models and humans at the higher dose of 2 mg/kg. Two new metoclopramide formulations are being clinically developed and they differ mainly in whether the pH of their formulations are acidic (pH 2.5-3.5) or neutral (pH 6.5-7.0). Here we report that intramuscular administration of neutral metoclopramide is about 100% bioavailable, safer and with reduced side effects compared to acidic metoclopramide delivered by intramuscular injection to rats within the dose range of 3.5 to 14 mgikg. The intramuscular administration of metoclopramide was also about 100% bioavailable compared to the intravenous route of administration. Furthermore, neutral metoclopramide had significantly decreased affinity for dopamine D2 receptors and increased affinity for 5-hydr~xytryptamine~ receptors, but the radiosensitizing potency was the same, when compared to equimolar concentrations of acidic metoclopramide. Taken together these data support the continued development of neutral metoclopramide for high dose intramuscular administration of metoclopramide for future clinical use as both an antiemetic and radiosensitizer.

Toxicity, Antitumor and Chemosensitizing Effects of 3-Chloroprocainamide

“…The same efficacy in retardation of tumor growth was found between neutral MCA and 3-CPA. they were equipotent (12). MCA has also been shown to chemosensitize cisplatin in vivo (6, 15).…”

“…These hydrogen bonds convert MCA into a condensed conformation and hence there is a greater affinity to D2 receptors. By adjusting the pH from 2.5-3.5 to 6.7-7.0. the neutralized MCA has been shown to have the same radiosensitizing efficacy as acidic MCA in enhancement of cytotoxicity in vitro (12)(13)(14) or in vivo induced by radiation in scid mice xenografted with a human lung adenocarcinoma (7.8) while having reduced sedation in the rat (12,13) and reduced extrapyramidal side effects in humans (36). The reduced side effect of neutral MCA is believed to be associated with a reduced affinity for the D, receptors due to the hydrolysis of the pH sensitive hydrogen bond and a more extended MCA molecule conformation (Schwartz & Pero.…”

“…This was clearly unexpected since 4-5 mg/ml i.m. injected MCA in the rat caused severe local tissue reactions (12,37). The reason for this discrepancy is currently unknown, but it should be pointed out that scid mice are immunodeficient and there may be less of an inflammatory reaction at the injection site for these animals.…”

Drug Evolution Concept in Drug Design: 2. Chimera Method

“…A pain-relieving effect of metoclopramide was recorded even in the treatment of ureteral colic [166]. As an inducer of DNA strand break and inhibitor of DNA repair [167], metoclopramide is a radiosensitizer which potentiates radiation-induced cytotoxicity [168] in its acidic formulation Primperan ® or better as a novel neutral formulation Neu-sensamide [169]. Moreover, metoclopramide also acts a chemosensitizer that modulates the antitumor effects of cisplatin [170] presumably by increased formation of cisplatin-DNA adducts [171].…”

Core-shell structure alginate-PLGA/PLLA microparticles as a novel drug delivery system for water soluble drugs

“…With regards to drug delivery however, it is limited in terms of sustained release of low molecular weight drugs due to the propensity of hydrogels to swell in water, as a result of its porosity when immersed in an aqueous environment [10,35] [36]. It is also reported to function as a radio-sensitizer and chemo-sensitizer for lung carcinoma treatment [37,38].…”