title: Substantially increased sildenafil bioavailability after sublingual administration in children with congenital heart disease: two case reports.
abstract: BACKGROUND
  Pulmonary hypertension is a progressive disease of diverse origin with devastating consequences in adults as well as in children. The phosphodiesterase 5 inhibitor sildenafil successfully lowers pulmonary vascular resistance. However, because of its poor enteral absorption, resulting in ineffective plasma concentrations, responses in infants and children are often erratic.
  
  
  METHODS
  We report the cases of two Caucasian boys, one born at term (case 1) and one aged 2.5 years (case 2), who had structural cardiac and pulmonary defects accompanied by symptomatic pulmonary hypertension. They received sildenafil enterally and sublingually and also intravenously in one of them. Plasma samples were taken at various time points to determine the plasma concentrations of sildenafil and its partially active metabolite. Sildenafil and N-desmethyl sildenafil were quantified using a validated liquid chromatography/mass spectrometry method. Oxygen partial pressure was determined from routine arterial blood gas samples.
  
  
  CONCLUSIONS
  In agreement with previous observations in adults, we found that sublingual sildenafil was more extensively absorbed in our two pediatric patients. After sublingual administration, sildenafil plasma concentrations increased by 314% to 361% compared to enteral dosing. Concurrently, the metabolic ratio increased, suggesting not only that the overall absorption was enhanced but also that first-pass metabolism was partially bypassed. In case 2, the free fraction of sildenafil was 0.9%, which is considerably less than in adults (4%), suggesting that, in case 2, higher plasma concentration would have been needed to achieve effects similar to those in adults. Sublingual sildenafil appears to be a promising alternative route of administration in children with poor enteral absorption.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Carls
authors.forename: Julia
authors.initials: J
authors.lastname: Winter
authors.forename: Yeliz
authors.initials: Y
authors.lastname: Enderle
authors.forename: Jürgen
authors.initials: J
authors.lastname: Burhenne
authors.forename: Matthias
authors.initials: M
authors.lastname: Gorenflo
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. WalterEmil.Haefeli@med.uni-heidelberg.de.
authors.forename: Walter E
authors.initials: WE
authors.lastname: Haefeli
mesh_terms: D000286:Administration, Sublingual; D001682:Biological Availability; D002675:Child, Preschool; D006330:Heart Defects, Congenital / Q000150:complications / Q000378:metabolism*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000209:etiology; D007231:Infant, Newborn; D008297:Male; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011687:Purines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate