A rapid and sensitive liquid chromatography/tandem mass spectrometry method for determination of docetaxel in human plasma.

A novel, rapid and sensitive isocratic liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed for quantification of docetaxel in human plasma with paclitaxel as internal standard. The high sensitivity and specificity of MS/MS detection enabled the use of a small volume of plasma (0.05 mL) and a simple liquid-liquid extraction procedure. Furthermore, a very short run-time (3 min) fulfilled the need for monitoring plasma levels of docetaxel from large-scale clinical studies. The calibration curve for docetaxel was linear over the range 5-1000 ng/mL with coefficients of correlation >0.999 using only 0.05 mL plasma. The intra- and inter-day precisions (CV) of analysis were <7%, and accuracy ranged from 96 to 110%. The applicability of the method was demonstrated in a pharmacokinetic study of a 1-h infusion of docetaxel with dosages of 75 mg/m(2). Possible conjugated metabolites of docetaxel were not detected in patients' samples.

Clinical evaluation and plasma clozapine concentrations in Chinese patients with schizophrenia.

The relationships between clozapine dosages, plasma concentrations, and clinical responses in Chinese schizophrenics were studied. Fourteen treatment-refractory schizophrenic patients were treated with clozapine for 12 weeks. Patients were assessed before and after 6 and 12 weeks of treatment using the Brief Psychiatric Rating Scale (BPRS), the Clinical Global Impression (CGI), and the Simpson-Angus Scale for Extrapyramidal Side Effect. Plasma clozapine concentrations were determined by high-performance liquid chromatography. Ten patients (71.4%) responded after 12 weeks of treatment. Although the mean daily dosage at week 12 (373 +/- 90 mg/day) was lower than that reported in American trials (444 mg/day), the mean plasma clozapine concentration attained (1,078 +/- 385 ng/ml) was higher. This higher concentration may be due to the lower body wight and the preponderance of women among our patients, absence of smoking and alcohol use, and/or ethnic difference between Chinese and non-Chinese. There was wide interindividual variation in the plasma clozapine concentrations. Compared with other studies, the plasma clozapine concentrations and the response rate were higher. Although the sample size was small, the findings are suggestive of pharmacokinetic and pharmacodynamic ethnic differences in Chinese with clozapine therapy.

Disposition of intravenous metronidazole in Asian surgical patients.

Steady-state peak and trough concentrations of metronidazole and its metabolites were measured in the sera of 54 surgical patients who were on intravenous metronidazole, 500 mg every 8 h. These patients had no significant renal or hepatic impairment. High-pressure liquid chromatography was used to determine the concentrations of metronidazole and its metabolites. The mean peak and trough metronidazole concentrations were 28.9 +/- 11.0 and 18.0 +/- 9.9 micrograms/ml, respectively. The acid metabolite was not detectable in all the blood specimens. The mean peak concentration of the hydroxy metabolite (MH) was 6.6 +/- 4.3 micrograms/ml, the mean trough concentration of MH was 6.2 +/- 4.2 micrograms/ml, and the MH concentration/metronidazole concentration ratio was 0.4 +/- 0.24. Using a population-based method for the pharmacokinetic analysis and stepwise regression between parameters and covariables (sex, age, and weight), we found that weight showed the highest correlation with the total body clearance (CL). The mean CL was 0.89 +/- 0.3 ml min-1 kg-1 (3.029 liters/h), the mean volume of distribution was 0.73 +/- 0.14 liter/kg, and the mean elimination half-life was 10.6 +/- 4.5 h. For the patients in our study, the CL was lower and the elimination half-life was longer compared with those for healthy volunteers, but the values of these parameters were comparable to those found for hospitalized patients. There was an inverse correlation between age and CL.

Simple HPLC determination of the concentrations of epiroprim in the serum and brains of mice.

Epiroprim, an analogue of trimethoprim, has been shown to potentiate the efficacy of dapsone in experimental parasitic infections. A simple and accurate HPLC method has been developed to estimate epiroprim in serum and brain. Blood and brains from mice were sampled 0, 30, 75, 120 and 240 min after 50 or 100 mg kg-1 oral gavage. The drug and added internal standard metoprine in serum and brain supernatant were isolated by solid-phase extraction (Superclean LC-SCX). The HPLC system consisted of a 150 x 4.6 mm Hypersil 5 microns ODS column. The mobile phases contained various proportions of acetonitrile, methanol and phosphate buffer (0.1 M). Peaks were detected by UV absorbance at 210 nm. Serum concentrations (mean +/- s.e.m.) of epiroprim were highest at 30 min for both 50 and 100 mg kg-1 doses, 173 +/- 20 and 207 +/- 25 ng mL-1, respectively, falling to 8 +/- 5 and 18 +/- 6 ng mL-1, respectively, at 240 min. Epiroprim concentrations in the brain correlated well with those in the serum, with levels of 223 +/- 69 and 265 +/- 21 ng g-1 falling to 10 +/- 10 and 31 +/- 11 ng g-1, respectively. Epiroprim is rapidly absorbed and distributed to the brain.

Paracetamol and its metabolites in saliva and plasma in chronic dialysis patients.

1. Many pharmacokinetic studies on paracetamol are based on saliva paracetamol concentrations. The utility of saliva in patients with chronic renal failure is unclear. In this study, concentrations of saliva and plasma paracetamol and its major metabolites, sulphate and glucuronide conjugates were determined at 0.5, 1, 2 and 3 h after the ingestion of 1 g paracetamol in 20 patients with endstage renal failure. Ten haemodialysis patients were studied on a non-haemodialysis day and during a haemodialysis session. The other 10 patients were on chronic ambulatory peritoneal dialysis. 2. The plasma paracetamol concentrations attained in all groups were not different from those reported previously in healthy subjects. Mean +/- s.d. plasma paracetamol concentrations at 0.5 h in haemodialysis patients on a non-haemodialysis day, during haemodialysis and in those on chronic ambulatory peritoneal dialysis were 15.3 +/- 8.2, 21.5 +/- 10.9 and 18.2 +/- 12.3 micrograms ml-1 respectively. 3. The saliva paracetamol concentrations were highly variable and unpredictable. Saliva paracetamol concentrations at 1, 2 and 3 h after ingestion in the haemodialysis group during haemodialysis were 31.5 +/- 20.1, 14.1 +/- 10.4 and 7.3 +/- 3.8 micrograms ml-1 respectively, significantly (P < 0.05; paired t-test) higher than the corresponding plasma paracetamol concentrations which were 11.0 +/- 2.8, 6.5 +/- 2.8 and 3.2 +/- 0.9 micrograms ml-1 respectively. 4. Correlation coefficients between saliva and plasma paracetamol concentrations in haemodialysis patients on a non-haemodialysis day and during haemodialysis and in chronic ambulatory peritoneal dialysis patients were poor; r = 0.58 (P < 0.0002); r = 0.40 (P < 0.02); and r = 0.13 (P = 0.49) respectively. 5. Three hours after paracetamol ingestion, plasma paracetamol, sulphate and glucuronide concentrations were significantly (P < 0.05) reduced in haemodialysis patients during haemodialysis when compared with the same patients on a non-haemodialysis day (paired t-test) and to the chronic ambulatory peritoneal dialysis group (Kruskal-Wallis ANOVA) except for plasma glucuronide. This indicates the effective removal of paracetamol and metabolites by haemodialysis. In contrast, chronic ambulatory peritoneal dialysis seemed to remove glucuronide only. 6. In the light of the poor correlation between saliva and plasma paracetamol in dialysis patients in this study, we would like to caution against using saliva paracetamol concentrations for pharmacokinetic studies in this group of patients.

Pharmacokinetics of propofol infusion in Asian patients undergoing coronary artery bypass grafting.

The pharmacokinetics of propofol was studied in 11 Asian patients with fentanyl-isoflurane anaesthesia during cardiopulmonary bypass (CPB) and undergoing elective coronary artery bypass grafting (CABG). Instead of the usual increments of morphine and a benzodiazepine, propofol (4 mg/kg/h) was initiated at the start of CPB and ceased at CPB separation. Whole blood propofol concentrations were determined during and postinfusion using high-performance liquid chromatography with fluorescence detection. Data from four patients seemed to fit a two-compartment model, whereas those from seven patients were significantly (F test, p < 0.05) better fitted to a three-compartment model. The pharmacokinetic parameters were as follows: The mean (SD) of the initial distribution phase t1/2 pi, intermediate distribution phase t1/2 alpha, and elimination phase t1/2 beta were 2.22 (1.04) min, 42.9 (16.4) min, and 370 (138) min, respectively. The mean clearance of 1.31 (0.50) L/min was lower than those reported from other studies, whereas the mean blood concentration of 2.2 (1.0) mg/L at the 1-h infusion period was higher. The mean calculated apparent Css was 3.9 (1.5) mg/L. The low clearance is likely to be due to hemodynamic changes during CPB and CABG, thereby affecting drug distribution and blood flow to the liver.

Clinical evaluation and serum concentration of zuclopenthixol acetate in psychotic Asian patients: a single-dose preliminary study.

Nineteen acutely disturbed psychotic Asian patients were treated with a single intramuscular injection of 50 mg of zuclopenthixol acetate in Viscoleo. Patients were assessed clinically before and after treatment using the Brief Psychiatric Rating Scale (BPRS). Serum zuclopenthixol and the inactive geometric isomer trans(E)-clopenthixol were determined by high-performance liquid chromatography after intramuscular injection. All patients improved, with the BPRS being significantly reduced (p < 0.001) at 72 h after injection. Adverse effects were generally few. The mean +/- SEM serum zuclopenthixol concentrations at 24, 48, and 72 h were 19.9 +/- 2.8, 31.5 +/- 4.5, and 17.8 +/- 2.9 micrograms/L, respectively. trans(E)-Clopenthixol concentrations ranged from negligible to 39.5 micrograms/L. This study confirms that a single intramuscular injection of 50 mg is adequate for managing severely disturbed psychotic patients for the first 3 days. The serum zuclopenthixol concentrations attained in the Asian patients were higher than those reported in Caucasian psychiatric patients. In some patients, a considerable amount of zuclopenthixol had been transformed to trans(E)-clopenthixol.

Tussock moth dermatitis: evidence for histamine involvement.

Moth hairs shed by the few tussock moths caught during the first documented outbreak of pruritic dermatitis in Singapore were investigated to provide evidence for the presence of histamine. Aqueous extract of the moth hairs was used for the test and analyses. In the isolated guinea pig ileum, the extract, like histamine, produced responses that were blocked by mepyramine. The high performance liquid chromatographic (HPLC) analysis of the fluorescamine derivative of the moth extract resulted in a fluorescent peak with exactly the same retention. time as the histamine fluorescamine derivative. The mass spectrum of the pentafluoropropionic acid (PFP) derivative of the extract was also identical to that obtained from the reference histamine-PFP derivative. We concluded that histamine was present in the tussock moth hairs and was involved as one of the inflammatory mediators responsible for the pruritic skin rashes.

A simple high-performance liquid chromatography method for measuring serum cloxacillin in eight Asian patients.

A simple reversed-phase high-performance liquid chromatography method using probenecid as internal standard was used for the quantitation of serum cloxacillin in eight Asian patients. The method does not require the extraction of the antibiotic from serum and the percentage recovery of cloxacillin was 96-103%. The presence of ampicillin, fusidic acid, benzylpenicillin, and gentamicin in serum appeared not to interfere with the method. The day-to-day coefficient of variation of the method over 6 months for 4-120 micrograms/ml ranged between 6.2 and 11.5%. In the eight patients in whom cloxacillin was administered intravenously or orally, there was great interindividual and intra-individual variation in the serum concentrations attained. The highest concentration of 85 micrograms/ml was obtained in a sample taken 1.5 h after an intravenous dose of 1 g. The lowest concentration of less than 1 microgram/ml was from a sample taken 6 h after an oral dose of 500 mg.