Pharmacokinetics of oxycodone after intravenous, buccal, intramuscular and gastric administration in children.

OBJECTIVE: To evaluate the pharmacokinetics of four administration routes of oxycodone parenteral liquid (10 mg/mL), single intravenous and intramuscular injections and buccal and gastric administration, in children. PATIENTS AND PARTICIPANTS: Forty generally healthy children, aged 6-93 months, undergoing inpatient surgery. METHODS: After induction of anaesthesia, children received a single dose of oxycodone 0.1 mg/kg intravenously (n = 9), intramuscularly (n = 10), buccally (n = 11) or via an orogastric tube into the stomach (n = 10). Regular blood samples were collected up to 12 hours, and plasma was analysed for oxycodone using gas chromatography-mass spectrometry (limit of quantification 1 microg/L). RESULTS: The peak drug concentration observed was 57-110 (mean 82) microg/L after intravenous administration, 23-54 (34) microg/L after intramuscular administration, 3.9-14 (9.8) microg/L after buccal administration and 1.7-15 (9.2) microg/L after gastric administration. The time to peak concentration was 2-30 (16) minutes in the intramuscular group, 30-480 (221) minutes in the buccal group and 60-360 (193) minutes in the gastric group. The terminal elimination half-lives were closely similar in the four groups: 124-208 (163) minutes in the intravenous group, 162-227 (150) minutes in the intramuscular group, 73-234 (150) minutes in the buccal group and 80-246 (147) minutes in the gastric group. Area under the concentration-time curve (AUC) was 5037-8954 (6612) microg x min/L in the intravenous group, 3084-5524 (4473) microg x min/L in the intramuscular group, 1444-5560 (3658) microg x min/L in the buccal group and 692-3843 (2436) microg x min/L in the gastric group. The estimated bioavailability (AUC/mean intravenous AUC) of intramuscular oxycodone was 0.47-0.84 (0.68), that of buccal oxycodone 0.22-0.84 (0.55) and that of gastric oxycodone 0.10-0.58 (0.37). CONCLUSION: The pharmacokinetics of intravenous oxycodone in children aged 6-93 months are fairly similar to those reported in adults. Intramuscular administration provides relatively constant drug absorption, but after buccal and gastric administration the interindividual variation in the rate and extent of absorption is large.

Paracellular and passive transcellular permeability in immortalized human corneal epithelial cell culture model.

A cell culture model of human corneal epithelium (HCE-model) was recently introduced [Invest. Ophthalmol. Vis. Sci. 42 (2001) 2942] as a tool for ocular drug permeation studies. In this study, passive permeability and esterase activity of the HCE-model were characterised. Immortalised human corneal epithelial cells were grown on collagen coated filters under air-lift. The sensitivity of transcellular permeability to lipophilicity was tested in studies using nine beta-blockers. The size selectivity of the paracellular route was investigated using 16 polyethylene glycol oligomers (PEG). An effusion-like approach was used to estimate porosity and pore sizes of the paracellular space in HCE membrane. Permeability and degradation of fluorescein diacetate to fluorescein in HCE-cells was used to probe the esterase activity of the HCE-model. Drug concentrations were analyzed using HPLC (beta-blockers), LC-MS (PEGs), and fluorometry (fluorescein). Permeabilities were compared to those in the excised rabbit cornea. Penetration of beta-blockers increased with lipophilicity according to a sigmoidal relationship. This was almost similar to the profile in excised cornea. No apical to basolateral directionality was seen in the permeation of beta-blockers. Paracellular permeability of the HCE-model was generally slightly higher than that of the excised rabbit cornea. The HCE-model has larger paracellular pores, but lower pore density than the excised cornea, but the overall paracellular space was fairly similar in both models. The HCE-model shows significant esterase activity (i.e. fluorescein diacetate was converted to free fluorescein). These data on permeability of 27 compounds demonstrate that the barrier of the HCE-model closely resembles that of the excised rabbit cornea. Therefore, the HCE-model is a promising alternative corneal substitute for ocular drug delivery studies.

Pharmacokinetics of intravenous and rectal ketoprofen in young children.

OBJECTIVE: To evaluate the relative bioavailabilities of ketoprofen after intravenous and rectal administration to young children. DESIGN: Open-label prospective parallel-group study. PATIENTS: Participants were 28 children aged 7 to 93 months. METHODS: Eighteen children received a single intravenous injection of ketoprofen 1 mg/kg, and ten children, weight 16-24 kg, received a 25mg ketoprofen suppository. Venous blood samples were collected at selected times after administration, ranging from 2 minutes to 8 hours for the intravenous group and from 30 minutes to 8 hours for the suppository group. A validated high performance liquid chromatography method was used to measure plasma ketoprofen concentrations. RESULTS: In the intravenous group, the maximum plasma concentration of ketoprofen ranged between 10.5 and 22.2 mg/L, and in the suppository group, following dose normalisation to 1 mg/kg of ketoprofen, between 3.8 and 7.4 mg/L. In the intravenous group, area under the concentration-time curve from zero to infinity ranged between 9.2 and 23.5 mg x h/L, and in the suppository group after dose normalisation between 8.8 and 12.9 mg x h/L. The bioavailability of ketoprofen from the suppository was about 73%. Volume of distribution was 0.04-0.10 L/kg in the intravenous group and 0.08-0.16 L/kg in the suppository group. The terminal half-life was comparable in both study groups, ranging between 0.7 and 3.0 hours in the intravenous group and between 1.2 and 2.9 hours in the suppository group. CONCLUSION: Absorption of ketoprofen after rectal administration is reasonably rapid and predictable. Because the bioavailability of rectal ketoprofen is also relatively high, a suppository may be used in children in whom the drug cannot be given intravenously or by mouth.

Extracellular and intracellular factors influencing gene transfection mediated by 1,4-dihydropyridine amphiphiles.

Double-charged 1,4-dihydropyridine (1,4-DHP) amphiphiles have been shown to condense DNA and efficiently transfect it into cells in vitro [Hyvönen et al., Biochim. Biophys. Acta 1509 (2000) 451]. Alkyl chain length and buffering capacity at endosomal pH range (5.0-7.4) affected complexation and transfection activity. In this study we examined how those chemical modifications of amphiphile-DNA complexes (amphiplexes) affect their interactions with extracellular polyanions (glycosaminoglycans, albumin) and lipid bilayers, their cellular uptake and intracellular distribution. To evaluate cellular uptake, CV1-P cells were incubated with labeled DNA-amphiphile complexes and analyzed by flow cytometry. Confocal laser fluorescence microscopy was used to investigate the intracellular distribution of amphiplexes. The results showed that biophysical properties of compounds can be changed by slight structural modifications. These factors determine the intracellular kinetics and transfection efficacy of the compounds. Some extracellular glycosaminoglycans and serum interfere with 1,4-DHP-amphiphile-mediated transfection by destabilizing the amphiplexes. Neither high cellular uptake, membrane destabilizing activity nor buffering capacity alone is adequate for high transfection efficacy. The activity results from complex interplay of various factors that determine intracellular kinetics and, consequently, transfection.