title: Cimetidine-associated patent ductus arteriosus is mediated via a cytochrome P450 mechanism independent of H2 receptor antagonism.
abstract: Persistent patency of the ductus arteriosus (PDA) is a common problem in preterm infants. The antacid cimetidine is a potent antagonist of the H2 histamine receptor but it also inhibits certain cytochrome P450 enzymes (CYPs), which may affect DA patency. We examined whether cimetidine contributes to PDA and is mediated by CYP inhibition rather than H2 blockade. Analysis of a clinical trial to prevent lung injury in premature infants revealed a significant association between cimetidine treatment and PDA. Cimetidine and ranitidine, both CYP inhibitors as well as H2 blockers, caused relaxation of the term and preterm mouse DA. CYP enzymes that are inhibited by cimetidine were expressed in DA subendothelial smooth muscle. The selective CYP3A inhibitor ketoconazole induced greater DA relaxation than cimetidine, whereas famotidine and other H2 antagonists with less CYP inhibitory effects caused less dilation. Histamine receptors were developmentally regulated and localized in DA smooth muscle. However, cimetidine caused DA relaxation in histamine-deficient mice, consistent with CYP inhibition, not H2 antagonism, as the mechanism for PDA. Oxygen-induced DA constriction was inhibited by both cimetidine and famotidine. These studies show that antacids and other compounds with CYP inhibitory properties pose a significant and previously unrecognized risk for PDA in critically ill newborn infants.
authors: Department of Pediatrics, Vanderbilt University School of Medicine and the Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, TN 37232, USA.
authors: Robert B
authors: RB
authors: Cotton
authors: Lisa P
authors: LP
authors: Shah
authors: Stanley D
authors: SD
authors: Poole
authors: Noah J
authors: NJ
authors: Ehinger
authors: Naoko
authors: N
authors: Brown
authors: Elaine L
authors: EL
authors: Shelton
authors: James C
authors: JC
authors: Slaughter
authors: H Scott
authors: HS
authors: Baldwin
authors: Bibhash C
authors: BC
authors: Paria
authors: Jeff
authors: J
authors: Reese
mesh_terms: D002927:Cimetidine / Q000009:adverse effects*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004374:Ductus Arteriosus, Patent / Q000139:chemically induced* / Q000378:metabolism*; D006635:Histamine H2 Antagonists / Q000009:adverse effects*; D006801:Humans; D007150:Immunohistochemistry; D007231:Infant, Newborn; D007654:Ketoconazole / Q000009:adverse effects; D016133:Polymerase Chain Reaction; D016032:Randomized Controlled Trials as Topic; D011899:Ranitidine / Q000009:adverse effects; D011968:Receptors, Histamine / Q000378:metabolism; D012189:Retrospective Studies
chemical_list: D006635:Histamine H2 Antagonists; D011968:Receptors, Histamine; D002927:Cimetidine; D011899:Ranitidine; D003577:Cytochrome P-450 Enzyme System; D007654:Ketoconazole