Caffeine has been used frequently in the treatment and prevention of apnea of prematurity. The metabolism of caffeine depends on the activities of the hepatic enzymes that vary from one infant to another. The objective of this study was to determine the influence of postnatal age (PNA), birth weight (BW), study weight (SW), gestational age (GA), postconceptual age (PCA), and gender on the maturation of caffeine metabolism in premature infants. The caffeine base was administered orally as a loading dose of 10 mg/kg, followed by a maintenance dose of 2 mg/kg every 24 hours. The steady-state concentration of caffeine and metabolites was measured in plasma taken on the 5th-day postloading dose. The molar concentration ratios for the N3 (N3-), N7 (N7-), N1 (N1-), and all methyl (Nall-) demethylation processes; clearance (CL); and the percentage of molar concentration of caffeine found in plasma to that of the total caffeine and metabolites (%CAF) were calculated from samples collected from 80 neonatal infants. The 48 male and 32 female premature infants had median (range) BW (g), GA (weeks), SW (g), PCA (weeks), and PNA (days) of 1300 (650-2260), 30 (24-34), 1630 (980-2670), 34 (29-40), and 28 (5-60), respectively. The median (range) of the ratios for the %CAF, CL, and the N3-, N7-, N1-, and Nall- were 86.9 (52.9-99.0), 0.127 (0.046-0.503) ml.kg-1.min-1, 0.032 (0-0.438), 0.070 (0.007-0.471), 0.026 (0-0.283), and 0.0463 (0.003-0.303), respectively. When the patients were stratified into four PNA age groups, each older group showed a consistently higher level of caffeine metabolic activity for the N3-, N7-, and Nall- pathways with a corresponding decrease in the %CAF, whereas no significant differences were seen for the N1-pathway or for CL. No pattern of significant differences between the demethylation process ratios, %CAF, or CL was seen between groups of infants when they were stratified according to BW, SW, PCA, or GA. The female infants were found to have significantly higher rates of caffeine metabolism as shown by %CAF, N1-, N3-, and Nall- processes but not the N7-. Multivariate linear regression analysis by two methods demonstrated that PNA is significantly related to %CAF and Nall-, whereas the female patients had higher levels of metabolic activity for the %CAF and N1- process. The authors conclude that the N7-demethy-lation process is the predominate caffeine metabolic process in premature infants. Furthermore, the maturation of the caffeine metabolism in premature infants with a PNA of less than 60 days increases with postnatal age, regardless of birth weight, gestational age, postconceptual age, and study weight. The female neonatal patients demonstrated a higher rate of caffeine metabolism than the males.

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Summary:The urinary excretion and pharmacokinetics of acrolein (ACRO) and its parent drug cyclophosphamide (CP) were investigated in 16 randomly selected bone marrow transplant (BMT) recipients when CP was used for conditioning. Patients suffering from aplastic anemia (n = 3) received a 4-day course of CP at a dose of 50 mg/kg daily infused intravenously (i.v.) over 1 h. Patients with leukemia (n = 13) were given either a combination of busulphan followed by CP at a dose of 50 mg/kg infused i.v. over 1 h for 4 days, or CP at a dose of 60 mg/kg by i.v. infusion over 1 h daily for 2 days followed by total body irradiation. Serial plasma samples and urine were collected after the start of the first CP dose. CP was analyzed by capillary gas chromatography, whereas ACRO was measured in urine by Cyclophosphamide (CP) is an alkylating agent which requires metabolic activation to exhibit its antineoplastic and immunomodulating activities. Some of the metabolites formed are thought to cross-link with cellular DNA and thereby interfere with proliferation and ultimately lead to cell death. In bone marrow transplantation (BMT), CP is currently playing a major role as part of conditioning regimens. This treatment allows acceptance of the graft in allogenic BMT and serves in allo-as well as autologous BMT to eradicate malignant cells or create space in the marrow cavity. CP undergoes complicated metabolism involving several pathways in vivo. 1 The main pathway involves hydroxylation of CP by hepatic microsomal oxidases to form 4-hydroxy-cyclophosphamide (4OH-CP) which is in equilibrium with its acyclic tautomeric form, aldophosphamide (ALDO). These metabolites are transport forms of CP. Oxidation of ALDO by aldehyde dehydrogenase results in the noncytotoxic metabolite carboxyphosphamide. Dehydrogenation of 4OH-CP gives another inactive metabolite, 4-keto cyclophosphamide. The final stage of activation, which takes place in cells that are susceptible, involves cleavage of 4OH-CP/ALDO by a ␤-elimination reaction to yield phosphoramide mustard and ACRO both of which are highly cytotoxic and represent active forms of the drug. One of the major dose-limiting side-effects of CP is hemorrhagic cystitis (HC) 2 which has been attributed to the urinary excretion of its metabolites, particularly ACRO. [3][4][5] Hemorrhagic cystitis which occurs in a somewhat unpredictable way, may be the result of altered pharmacokinetics of CP or elevated formation and/or variation in the renal excretion of ACRO. It may also be ascribed to inadequate urinary concentration of mesna, 5 a uroprotective agent used for neutralizing the damaging effect of ACRO by chelation.This study was undertaken to investigate the urinary excretion and pharmacokinetics of ACRO and its parent drug CP in BMT recipients when CP is used for conditioning, and to examine the relationship between hemorrhagic cystitis and urinary excretion of ACRO. Patients and methods Patient selectionA total of 16 patients ranging in age between 14 and 46 years were randomly selected among the ...

The authors describe a rapid, useful, specific, and very sensitive high-performance liquid chromatographic assay for the determination of fluvastatin (FV) level using atorvastatin as the internal standard (IS). After a simple deproteinization of 1.0 mL of plasma with acetonitrile, the drug and IS were extracted with tert-methyl butyl ether (TMBE). An efficient separation was performed using an 8 mm x 10 cm Nova Pak C(18) 4-microm particle size radial compression cartridge. The mobile phase consisted of an aqueous solution containing 20 mmol/L dibasic sodium dihydrogen phosphate with 1 mmol/L sodium lauryl sulfate adjusted to pH 7 with phosphoric acid and acetonitrile (70:30 v/v) delivered at a flow rate of 1.0 mL/min. The compounds of interest were detected using a fluorescence detector with the excitation wavelength set at 305 nm and the emission at 380 nm. Under these conditions, the retention times for FV and IS were 8.8 and 10.6 minutes, respectively. The concentration of FV in plasma was linear (r > 0.999) for the wide range that was examined (0.5-1,000 ng/mL). The recovery ranged from 88% to 96%. This sensitive, rapid, and simple analytical method gives accurate results over the wide range of concentrations examined. This method is used currently for clinical therapeutic monitoring and pharmacokinetic studies of FV in patients with hypercholesterolemia.

The steady-state pharmacokinetics of the atypical antipsychotic drug clozapine in schizophrenic Saudi Arabian patients was studied and correlated with the clinical outcome.Twenty-six schizophrenic patients were given clozapine over a period of 2±41 months. The daily dose ranged from 100 to 700 mg, and the frequency of administration varied from 1 to 2 times daily. A blood sample was collected from each patient at the midpoint of the dosing interval and was repeated on different days in six randomly selected patients to establish the steady-state condition. The concentration of clozapine in plasma (C ss ) was measured by HPLC with UV detection at 250 nm using C 18 bonded SepPak cartridges for sample preparation. The apparent oral clearance (CL p.o. ) was calculated from the equation: CL p.o. doseatC ss where t is the time between two consecutive doses. The effectiveness of the treatment was evaluated by the standard Positive and Negative Syndrome Scale (PANSS). The mean AE s.d. steady-state concentration (C ss ) was 491 AE 299 ng mL À1 . There were no signi®cant differences in C ss or any of the pharmacokinetic parameters studied between the 11 patients who responded positively to the treatment and the 15 patients who responded negatively.These results do not support the hypothesis that there is a positive correlation between higher plasma concentrations and positive response from clozapine in Saudi Arabian patients.

Measurement of salivary clearance and urinary metabolites of caffeine is an excellent noninvasive tool for assessing liver function, particularly the activity of cytochrome P4501A2 (CYP1A2), N-acetyltransferase (NAT), and xanthine oxidase (XO). This study was undertaken to measure the clearance of caffeine using saliva as a biological fluid and to assess the activities of the above-mentioned enzymes in healthy children and pediatric patients with liver diseases using urinary molar ratios of different caffeine metabolites. The well-established two-sample saliva approach was used to measure the clearance of caffeine in nine pediatric patients with liver diseases (LD) and in nine healthy children. The caffeine metabolites were also measured in the urine of these subjects by high-performance liquid chromatography, and urinary molar ratios of 5-acetylamino-6-formylamino-3-methyluracil (AFMU), 1-methylxanthine (1X), 1-methyluric acid (1U), and 1,7-dimethyluric acid (17U) were employed to estimate the activities of CYP1A2, NAT, and XO. The caffeine salivary clearance and the percentage of the dose excreted in the form of various metabolites were significantly (p < 0.035) smaller in the LD patients than those in healthy children. The urinary molar ratio of [AFMU + 1U + 1X]/17U, which reflects the activity of CYP1A2, was also significantly (p < 0.0005) reduced in these patients. However, there were no significant differences between the two groups in the ratios of AFMU/1X and 1U/1X, which estimate the activities of NAT and XO, respectively. In conclusion, the data obtained suggest that liver disease in pediatric subjects significantly reduces the salivary clearance of caffeine and the activity of cytochrome P4501A2, but it has no impact on the activities of NAT and XO.

The authors describe a useful and rapid micromethod for the analysis of itraconazole (ITZ) and its active metabolite hydroxyitraconazole (HIT) in human plasma. After a simple deproteinization of 100 microL plasma with acetonitrile, the drug, its metabolite, and an internal standard (IS, ketoconazole) were separated on an 8 mm x 10 cm NovaPak (Waters Associates; Milford, MA) C(18) 4-microm particle-size radial compression cartridge. The compounds of interest were detected using a fluorescence detector with the excitation wavelength set at 260 nm and the emission at 365 nm. The mobile phase consisted of 420 mL water adjusted to a pH of 2.5 with phosphoric acid, 580 mL acetonitrile, and 100 microL triethylamine, which was delivered at a flow rate of 3.0 mL/min. This expedient and rugged method is being used to monitor therapeutic levels in bone marrow transplant recipients who are taking the drug for prophylaxis.