title: Disposition of morphine in plasma and cerebrospinal fluid varies during neonatal development in pigs.
abstract: The pharmacological effects of morphine are mediated via the central nervous system (CNS) but its clearance from the CNS in neonates has not been investigated. We have proposed that neonatal development of the blood-brain barrier affected CNS clearance mechanisms and CNS exposure to morphine. Male piglets (n = 5) aged one, three and six weeks were given morphine sulfate (0.5 mg kg(-1), i.v.). Serial blood and cerebrospinal fluid (CSF) samples were withdrawn over 360 min after morphine administration. Morphine concentration was measured by radioimmunoassay. A three-compartment model was fitted to individual data. Estimated parameters were reported as median and range. The peak morphine concentrations in plasma were not significantly different in the one-, three- or six-week-old piglets. Plasma clearance at one week (4.5, 3.8-8.6 mL min(-1) kg(-1)) was significantly lower than at three weeks (30.0, 19.1- 39.0 mL min(-1) kg(-1)) and six weeks (37.0, 29.7-82.8 mL min(-1) kg(-1)). The peak morphine concentration in CSF at one week (59.84, 31-67 ng mL(-1)) was higher than at three weeks (18.8, 17.7-25 ng mL(-1)) and six weeks (24.51, 16.5-84 ng mL(-1)), while CSF clearance was lower at one week (1.0, 0.18-9 mL min(-1) kg(-1)) compared with three weeks (6.2, 2.3-9.3 mL min(-1) kg(-1)) and six weeks (3.95, 1.3-85.7 mL min(-1) kg(-1)). Apparent plasma:CSF transfer ratio at one week was greater than at three and six weeks. The reduced plasma and CSF morphine clearance in early infancy resulted in elevated systemic and central morphine exposure in neonatal pigs.
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, The University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Aarati
authors.initials: A
authors.lastname: Rai
authors.forename: Shaifali
authors.initials: S
authors.lastname: Bhalla
authors.forename: Sam S
authors.initials: SS
authors.lastname: Rebello
authors.forename: Helen
authors.initials: H
authors.lastname: Kastrissios
authors.forename: Anil
authors.initials: A
authors.lastname: Gulati
mesh_terms: D000375:Aging / Q000502:physiology*; D000701:Analgesics, Opioid / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000633:toxicity; D000818:Animals; D000831:Animals, Newborn; D048788:Growth and Development / Q000502:physiology*; D008297:Male; D009020:Morphine / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000633:toxicity; D009359:Neonatology; D013552:Swine
chemical_list: D000701:Analgesics, Opioid; D009020:Morphine