Potentially harmful excipients in neonatal medications: a multicenter nationwide observational study in Japan.

BACKGROUND: A multicenter investigation of neonate exposure to potentially harmful excipients (PHEs) in neonatal intensive care units (NICUs) in Japan has not been conducted. METHODS: A multicenter nationwide observational study was conducted. Neonate patient demographic data and information on all medicines prescribed and administered during hospitalization on 1 day between November 2019 and March 2021 were extracted from the medical records. Nine PHEs, paraben, polysorbate 80, propylene glycol, benzoates, saccharin sodium, sorbitol, ethanol, benzalkonium chloride, and aspartame, were selected. PHEs were identified from the package insert and the Interview Form. The quantitative daily exposure was calculated if quantitative data were available for each product containing the PHE. RESULTS: Prescription data was collected from 22 NICUs in Japan. In total, 343 neonates received 2360 prescriptions for 426 products containing 228 active pharmaceutical ingredients. PHEs were found in 52 (12.2%) products in 646 (27.4%) prescriptions for 282 (82.2%) neonates. Benzyl alcohol, sodium benzoates, and parabens were the most common PHEs in parenteral, enteral, and topical formulations, respectively. Quantitative analysis showed that 10 (10%), 38 (42.2%), 37 (94.9%), and 9 (39.1%) neonates received doses exceeding the acceptable daily intake of benzyl alcohol, polysorbate 80, propylene glycol, and sorbitol, respectively. However, due to the lack of quantitative information for all enteral and topical products, accurate daily PHE exposure could not be quantified. CONCLUSIONS: Neonates admitted to NICUs in Japan were exposed to PHEs, and several of the most commonly prescribed medicines in daily clinical practice in NICUs contained PHEs. Neonate PHE exposure could be reduced by replacing these medicines with available PHE-free alternatives.

Kinetic characterization of carrier-mediated transport systems for D-glucose and taurocholate in the everted sacs of the rat colon.

The present study was aimed at kinetically characterizing the carrier-mediated transport systems for D-glucose and taurocholate in the rat colon, compared with their respective counterparts in the small intestine. The transport of these compounds was evaluated by measuring the initial uptake into everted intestinal tissue sacs. The uptake of both D-glucose and taurocholate was highly saturable, conforming to Michaelis-Menten kinetics without an appreciable nonsaturable transport component. The Michaelis constant (K(m)) was 0.43 and 0.021 mM, respectively, for D-glucose and taurocholate and the maximum transport rate (J(max)) was 0.82 and 0.056 nmol/min/100 mg wet tissue weight (wtw), respectively. For both compounds, these values of K(m) and J(max) in the colon were one to three orders of magnitude smaller than those in the small intestine, suggesting that the transport systems in the colon have by far a higher affinity and a lower transport capacity than their counterparts in the small intestine. However, it is now evident from kinetic studies that carrier-mediated transport systems for D-glucose and taurocholate are also present in the colon. It will be interesting to explore the possibility that they could be used for oral drug delivery via the colon. Their physiological roles would also be of interest.

Search for carrier-mediated transport systems in the rat colon.

Several nutrients and drugs, which are known to be absorbed by specific carrier-mediated transport systems in the small intestine, had their transport investigated in the rat colon, by measuring uptake into everted sacs, to find if carrier-mediated transport systems may also be present in the colon. Among those transported by Na+-dependent carriers in the small intestine, D-glucose and taurocholate were found to be transported in an Na+-dependent manner in the colon, while 5-fluorouracil and ascorbate were not. It was also found that the colonic transports of D-glucose and taurocholate were saturable. These results suggest the presence in the colon of Na+-dependent carrier-mediated transport systems for D-glucose and taurocholate, but not for 5-fluorouracil and ascorbate. For nicotinate and methotrexate, which are transported by H+-dependent carriers in the small intestine, their transport was elevated at a lower pH (5.0) than the pH 7.4 in the colon, but not saturable. Therefore, the elevated transport of these acidic compounds may be explained by an increase in passive flux due to an increase in the fraction of the unionized and/or neutral forms, without postulating the presence of H+-dependent carrier-mediated transport systems in the colon. The transport activity of the suggested colonic transport systems for D-glucose and taurocholate was much lower than those of their respective counterparts in the small intestine. However, it may be possible to use them for oral drug delivery via the colon. Their physiological roles would also be of interest.