Plasma and cerebrospinal fluid concentrations of ibuprofen in pediatric patients and antipyretic effect: Pharmacokinetic-pharmacodynamic modeling analysis.

We aimed to determine the relationship between plasma and cerebrospinal fluid (CSF) concentrations of ibuprofen and the antipyretic effect in pediatric patients. A prospective cohort of infants and children aged 3 months to 15 years and treated with ibuprofen was studied. The patients received ibuprofen (via oral route, median dose of 10.0 mg/kg; 3.4-11.4 mg/kg range), samples of blood and CSF were collected, and body temperature was measured. Sequential analysis of the pharmacokinetic and pharmacodynamic data from 28 patients was performed using a population modeling approach. The observed concentration versus time data indicated substantial pharmacokinetic variability in absorption and distribution of ibuprofen between the patients. The pharmacokinetic modeling outcomes indicate that following a ∼25-minute lag time, ibuprofen is rapidly absorbed to the central compartment and rapidly equilibrates with the CSF, resulting in the total ibuprofen concentration in the CSF versus plasma (CCSF /Cplasma ) of 0.011 ± 0.007. The antipyretic effect of ibuprofen was best described by an indirect response PK-PD model incorporating patient baseline body temperature and ibuprofen concentration in the CSF. We conclude that the pharmacokinetic-pharmacodynamic modeling can be used to predict the time course of ibuprofen plasma and CSF concentrations and of the antipyretic effects in individual pediatric patients.

Cerebrospinal fluid distribution of ibuprofen after intravenous administration in children.

BACKGROUND: Ibuprofen is the most commonly used nonsteroidal, antipyretic, antiinflammatory analgesic in children. Nonsteroidal, antipyretic, antiinflammatory analgesics act in both the peripheral tissues and the central nervous system. The central nervous system penetration of ibuprofen has been described in adults but not in children. OBJECTIVES: Our goals were to investigate the cerebrospinal fluid penetration of ibuprofen in children and evaluate the analgesic plasma concentration of ibuprofen after inguinal surgery in children. MATERIALS AND METHODS: A total 36 healthy children (25 boys) aged 3 months to 12 years received a single intravenous injection of ibuprofen (10 mg/kg). A paired cerebrospinal fluid and blood sample was obtained 10 minutes to 8 hours after the injection. In children having inguinal surgery, a second blood sample was obtained at the time that the child first had wound pain. RESULTS: The ibuprofen level was determined in all cerebrospinal fluid and plasma samples. Cerebrospinal fluid concentrations ranged between 15 and 541 microg/L, and the highest concentrations were measured 30 to 38 minutes after dosing. In all cerebrospinal fluid samples collected after 30 minutes, ibuprofen concentration exceeded that of unbound plasma. The plasma analgesic concentrations after inguinal surgery ranged between 10 and 25 mg/L. CONCLUSIONS: Ibuprofen penetrates the cerebrospinal fluid readily, with peak concentrations attained 30 to 40 minutes after intravenous injection of a 10 mg/kg dose. The plasma analgesic concentration after inguinal surgery with spinal anesthesia is 10 to 25 mg/L.

A simple in vitro model to study the stability of acylglucuronides.

INTRODUCTION: Compounds containing the carboxylic functional group (e.g. non-steroidal anti-inflammatory drugs) can be metabolized to form acylglucuronides. Acylglucuronides are intrinsically reactive metabolites capable of undergoing hydrolysis, intra-molecular rearrangement, and formation of covalent adducts with proteins, which may generate potential toxicity. The purpose of this study is to develop an in vitro screening model to assess degradation kinetics of acylglucuronides. METHOD: Zomepirac, ibuprofen, gemfibrozil, and compounds A, B, C, and D were incubated in the presence of rat microsomal protein and uridine 5'-diphosphoglucuronic acid (UDPGA), followed by addition of human plasma to evaluate degradation kinetics of the acylglucuronides. As a comparison, authentic acylglucuronide standards of zomepirac, ibuprofen, gemfibrozil, and compounds A, B, C, and D were chemically synthesized and were evaluated for degradation kinetics. RESULTS: The results demonstrate that degradation half-life values of acylglucuronides of zomepirac, ibuprofen, gemfibrozil, and compounds A, B, C, and D determined by the in vitro formation/degradation model were in the same rank-order with those of the authentic acylglucuronide standards. DISCUSSION: For the seven compounds tested, the model placed the stability of the acylglucuronides formed in vitro in a rank-order consistent with authentic acylglucuronide standards. The method allows for a rapid assessment of the stability of acylglucuronides.

Stereoselective disposition of ibuprofen enantiomers in human cerebrospinal fluid.

Since both (R)- and (S)-enantiomers of ibuprofen may act on the central nervous system, we investigated their plasma and cerebrospinal fluid (CSF) concentrations in 46 patients with nerve-root compression pain requiring a lumbar puncture. Each patient received an oral dose of 800 mg rac-ibuprofen. A single blood and CSF sample was drawn concomitantly from each patient at intervals between 30 min and 8 h after dosing. Both isomers peaked later in the CSF (3 h) than in the plasma (1.5 h). Their CSF concentrations became higher than their concurrent free plasma concentrations after 90 min. The estimated elimination half-lives of (R)- and (S)-ibuprofen were 1.7 h and 2.5 h in plasma and 3.9 h and 7.9 h in CSF, respectively. The AUCCSF/AUCplasma ratios (0, 8 h) were 0.009 and 0.015 for the (R)- and (S)-forms, respectively.