The Pharmacokinetics of Sildenafil May Be Affected by Intestinal Absorption Rate in Children Admitted to the Intensive Care Unit

• Published in: Biological & pharmaceutical bulletin 2020/12/01, Vol.43(12), pp.1917-1923
• Main Authors: Oya, Yukino, Watahiki, Daisuke, Matsunaga, Mitsuki, Hirono, Keiichi, Ichida, Fukiko, Aoki, Masaya, Yoshimura, Naoki, Taguchi, Masato
• Format: Article
• Language: English
• Subjects: Bioavailability; child; Children; Duodenum; gastrointestinal motility; Intensive care; intensive care unit; Intestinal absorption; Intestine; Metabolites; Oral administration; Pharmacokinetics; Sildenafil
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b20-00614

This study was performed for a better understanding of the pharmacokinetics of sildenafil (SIL) and N-desmethyl sildenafil (DMS) in 13 children treated in the intensive care unit (ICU). Blood samples were taken periodically after the first oral administration of SIL (0.5 mg/kg). Plasma concentrations were analyzed by tandem LC/MS. Of the 13 patients, apparent peaks in the plasma concentration of SIL were observed in four patients, with the other nine patients showing reduced or delayed drug absorption of SIL. The maximum plasma concentrations of SIL after administration varied in range from 7.8 to 101.0 ng/mL. The parent drug-to-metabolite (SIL/DMS) ratios of the nine patients with reduced or delayed drug absorption of SIL were relatively lower than those in the four patients with rapid absorption of the drug. These observations suggested that the inter-individual variability of intestinal absorption and/or first-pass extraction of SIL was involved in the pharmacokinetic variability of the drug. Next, we evaluated the impact of changes in the gastrointestinal absorption rate on the pharmacokinetics of the drug. That is, SIL (2.5 mg/body) was administered at two different rates in the duodenum of rats. When SIL was administered for 10 min, the Cmax and bioavailability were 3.46 ± 1.65 µg/mL and 23.2 ± 11.1%, respectively. When SIL was administered for 60 min, the Cmax and bioavailability were 0.990 ± 0.352 µg/mL and 9.91 ± 3.79%, respectively. These findings suggest that the drug absorption rate was at least partly responsible for the pharmacokinetic variability of SIL in the ICU children.