Caffeine metabolism in premature infants.

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.

Optimization of oral etoposide dosage in elderly patients with non-Hodgkin's lymphoma using the fraction of dose absorbed measured for each patient.

This study was undertaken to investigate the pharmacokinetics of etoposide for optimizing its oral dosage in elderly patients with non-Hodgkin's lymphoma (NHL) using the fraction of dose absorbed calculated from the data generated from first oral and intravenous doses in the same patient. Twenty-three NHL patients (ages 61-95 years) entered this study. Each received 50 mg/m2 of etoposide by 1-hour i.v. infusion, which was repeated every 24 hours for 5 days. The second cycle commenced on day 21, with etoposide being administered by mouth at a dose as close to 50 mg/m2 as possible. Serial blood samples were collected and analyzed for etoposide by HPLC. The fraction of dose absorbed (F) was calculated as F = (AUCor/AUCi.v.) (Di.v./Dor), and etoposide was then given orally for the following 20 days at a daily dose equivalent to Dor/F. After 1 week free of etoposide administration, a second cycle of oral etoposide at the adjusted dose was given for 21 days. The mean +/- SD values for t1/2 beta, tmax, Cmax, CLTor, and MRT observed following the first oral dose were 8.98 +/- 4.84 h, 1.39 +/- 0.96 h, 0.083 +/- 0.046 mg.L-1/mg.m-2, 1.89 +/- 1.2 L.h-1/m2, and 10.37 +/- 2.76 h, respectively, and those observed following the first intravenous dose were 8.05 +/- 5.11 h, 1.57 +/- 0.17 h, 0.142 +/- 0.043 mg.L-1/mg.m-2, 1.25 +/- 0.44 L.h-1/m2, and 7.69 +/- 1.53 h, respectively. The mean +/- SD of F was 0.80 +/- 0.34. The data obtained indicate that optimization of etoposide oral dosage using F yielded good clinical results while keeping the morbidity at a level that is similar to that of the i.v. administration.

Pharmacokinetics of S- and R-enantiomers of aminoglutethimide following oral administration of racemic drug in breast cancer patients.

This study was undertaken to examine the pharmacokinetics of both enantiomers of AG--that is, (R-AG) and (S-AG) and respective acetyl metabolites, R-AcAG and S-AcAG--in breast cancer patients. Six patients received a single dose (500 mg) of the racemic drug, and serial plasma samples and urine were collected over a 48-hour period. R-AG, S-AG, R-AcAG, and S-AcAg were measured simultaneously by high-performance liquid chromatography using two serial chiral separation columns with ultraviolet detection. The plasma concentrations of R-AG were about 1.5 times higher than those of S-AG, and the data for both enantiomers exhibited the characteristics of the one-compartment open model. There were no significant differences between R- and S-AG in ka, tmax, V/F, and t1/2. The formation of R- and S-AcAG was rapid, and no correlation was found between the t1/2 values of the AG enantiomers with that of their acetylated metabolites. Overall, 41% of the dose was excreted in urine as AG (15% R-AG and 26% S-AG) and 5.1% as AcAG (2.9% R-AcAG and 2.2% S-AcAG). Renal clearance of S-AG was significantly greater (i.e., 2.3-fold) than that of R-AG and appears to be most likely the cause for the other pharmacokinetic differences observed. Both enantiomers had low renal extraction ratios, suggesting extensive tubular reabsorption of the compounds. However, based on the data obtained, it was concluded that the main factor contributing to the therapeutic effectiveness of racemic AG is the large potency difference between the R- and S- forms (R > S). The pharmacokinetic differences between R-AG and S-AG appear to contribute only marginally to the activity of this drug as an aromatase inhibitor.

Plasma and urinary selenium in Saudi Arabian patients with dilated cardiomyopathy.

We measured selenium (Se) levels in the urine and blood plasma samples of 72 Saudi Arabian patients with dilated cardiomyopathy (DCM) and 70 control subjects of the same origin. To correct for differences in the hydration state of the subjects, the selenium concentration for each urine sample was normalized by dividing it by the concentration of creatinine (CREAT) in the same sample. The median (and range) of the values found for the concentration of Se in plasma, urine, and normalized concentration in urine for the control subjects was 1.306 (0.66-2.50) microM, 0.478 (0.05-2.00) microM, and 56.7 (10.6-426.5) microM Se/M CREAT, respectively, whereas, for the patients, it was 1.246 (0.53-2.45) microM, 0.39 (0.05-1.90) microM, and 75.1 (4.9-656.2) microM Se/M CREAT, respectively. Additionally, the patients were separated into three subgroups according to the severity of their disease state as judged by NYHA procedure, and were then compared to the control group. Only group 4 (the most severe state of the disease) had a significantly lower concentration of urinary Se than the control group. However, the difference became nonsignificant when normalized for CREAT levels. There was no significant difference in the plasma Se levels between the controls and any of the patient groups. As the plasma Se in the control group and in the DCM patients both fell on the low end of the "normal" range, with the patients being marginally lower than the controls, there is no firm evidence from this study to suggest that Se is related to the high incidence rate of DCM found in Saudi Arabia.

Salivary clearance and urinary metabolic pattern of caffeine in healthy children and in pediatric patients with hepatocellular diseases.

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.

Pharmacokinetics of azithromycinin rabbit lacrimal glands and conjunctiv a.

PURPOSE AND BACKGROUND: To measure azithromycin levels in rabbit lacrimal and Harder glands, conjunctiva and plasma after a single oral dose of 20 mg/kg. Drug levels in lacrimal gland tissue are significant in trachoma because the gland may be involved in the disease process and it is the source of tears by which the drug is carried to the external eye. METHODS: Lacrimal and Harder glands, conjunctiva and plasma were collected from New Zealand white female rabbits at 24, 48, 72, 96 and 144 h following a single oral dose of azithromycin (20 mg/kg). Azithromycin levels in tissue and plasma were measured using high-performance liquid chromatography (HPLC) electrochemical detection. RESULTS: Azithromycin levels peaked within the first 24 h in all tissues and plasma assayed. The highest concentration was in the lacrimal gland (6.2 microg/g, SD +/- 0.8), followed by Harder gland (4.4 microg/g, SD +/- 0.8), conjunctiva (0. 9 microg/g, SD +/- 0.5) and plasma (0.06 microg/g, SD +/- 0.03). These concentrations reached their lowest measured levels at 120 and 144 h. CONCLUSION: Azithromycin levels measured throughout the 144 h after dosing were consistently above the minimum inhibitory range (MIC) for Chlamydia trachomatis (0.03-0.25 microg/ml) in the lacrimal glands, while the conjunctiva maintained a concentration above the MIC for 96 h and stayed within MIC levels for 144 h.

The role of selenium deficiency in dilated cardiomyopathy in Saudi Arabia.

BACKGROUND: Selenium deficiency is implicated in the etiology of endemic juvenile dilated cardiomyopathy in China, and in sporadic cases in other countries. The aim of this study was to evaluate the role of selenium deficiency in the pathophysiology of dilated cardiomyopathy in the Saudi Arabian population. PATIENTS AND METHODS: Plasma and urine selenium concentrations from 72 Saudi patients with confirmed dilated cardiomyopathy were compared with corresponding values from 70 control subjects of the same national origin who had normal ventricular function. RESULTS: Plasma and urine selenium concentrations (mean+/-SD) were 1.347plusmn;0.45 and 0.49+/-0.37 micromol/L, respectively, for the patient group, and 1.32+/-0.41 and 0.60+/-0.41 micromol/L, respectively, for the control group. The differences in the values between the two groups were statistically insignificant. CONCLUSION: In the Saudi population, dilated cardiomyopathy is not caused by selenium deficiency.

Simultaneous high-performance liquid chromatography analysis of azithromycin and two of its metabolites in human tears and plasma.

This article describes a high-performance liquid chromatographic (HPLC) method for the measurement of azithromycin (AZI) and two of its metabolites, 9a-N-desmethylazithromycin (ADES) and N-desmethylazithromycin (NDES), in human tears and plasma. The drug, metabolites, and internal standard (n-propylazithromycin [IS]) were detected electrochemically after injection of the extracted sample into the HPLC system. The peak height ratio (AZI, ADES, or NDES to IS) varied linearly, with concentrations in the ranges of 0.1 mg/L to 2.0 mg/L (tears) and 0.01 mg/L to 2.0 mg/L (plasma) of AZI, ADES, and NDES; the correlation coefficient (r) was more than 0.994 mg/L for all of the compounds (n=6). The analysis of tear samples collected at different intervals within 12 hours to 144 hours after a dose of 20 mg/kg of AZI from a trachoma patient yielded concentrations ranging from 1.52 mg/L to 0.34 mg/L for AZI, 0.79 mg/L to 0.27 mg/L for ADES, and 1.99 mg/L to less than 0.20 mg/L for NDES. The concentration of AZI in plasma ranged from 0.15 mg/L to 0.01 mg/L, whereas ADES and NDES were undetectable.

Ocular penetration of oral clarithromycin in humans.

Clarithromycin has a wide spectrum of activity against many gram-positive and gram-negative organisms, intracellular pathogens, and opportunistic pathogens. To examine the penetration of clarithromycin in the ocular tissues, 21 patients who underwent elective cataract surgery (Group I) received a single 500-mg dose of clarithromycin orally either 4, 8, 10, 12, or 22 hours before cataract surgery, and 21 patients who underwent elective retina/vitreous surgery (Group II) received 500 mg every 12 hours orally for 3 days before the surgery with the last dose given either 3, 6, 8, 11, or 24 hours before the surgery. Serum from all patients was assayed for clarithromycin prior to drug administration and at the time ocular specimen was taken. Aqueous, iris, and vitreous samples were also assayed for clarithromycin concentration. The concentrations of clarithromycin in the aqueous fluid 4, 8, 10, 12, and 22 hours after administration were: (mean +/- SD) 0.13+/-0.05, 0.137+/-0.11, 0.074+/-0.03, 0.06+/-0.02, and 0.074+/-0.04 microg/ml, respectively. Concentration of clarithromycin in vitreous 3, 6, 8, 11, and 24 hours after administration were: (mean +/- SD) 0.11+/-0.02, 0.257+/-0.13, 0.27+/-0.21, 0.307+/-0.26 and 0.108+/-0.07 microg/ml, respectively. The mean concentration of clarithromycin in the iris was 6.2 microg/g. In conclusion, this data suggest that clarithromycin widely penetrates and adequately concentrates in the aqueous humor, vitreous humor, and iris tissue after oral administration and therefore is effective in the management of many infectious ocular conditions.

Urinary excretion and pharmacokinetics of acrolein and its parent drug cyclophosphamide in bone marrow transplant patients.

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 liquid chromatography. The plasma concentration-time data for CP conformed to the two-compartment model and the mean and s.e.m. values of alpha, beta, Vss, total clearance, and renal clearance observed were 1.29 (0.31) h(-1), 0.17 (0.03) h(-1), 0.67 (0.13) l/kg, 0.14 (0.02) l/h x kg, and 0.0188 (0.0052) l/h x kg, respectively. The mean and s.e.m. values of fraction of CP excreted in the form of ACRO during this interval (fmu) and ratio of the 24-h urinary concentration of ACRO/creatinine (Cmu(n)) were 1.96 (0.35%) and 9.11 (2.19) microg of ACRO/mg of creatinine, respectively. Two patients developed hemorrhagic cystitis (HC). Each of these two patients excreted significantly (P < 0.01) more ACRO in the first and second 4-h urine collection periods. However, there was no significant difference in fmu or Cmu(n) of ACRO between either of these two patients and the rest. This suggests that the rate of appearance of ACRO in urine is more crucial for developing HC than the cumulative amount excreted.

Pharmacokinetics of azithromycin in trachoma patients: serum and tear levels.

OBJECTIVE: To determine the effectiveness of single-dose oral azithromycin in the treatment of Chlamydia trachomatis through monitoring of tear and serum levels. DESIGN: Nonrandomized, clinical trial. PARTICIPANTS: Fourteen school-age children with active trachoma (one failed to complete the study). INTERVENTION: A single dose of azithromycin (20 mg/kg) was administered orally to 14 patients, and tear and serum levels were determined with high-performance liquid chromatography at 12, 24, 48, 72, 96, 120, and 144 hours after administration. MAIN OUTCOME MEASURES: Azithromycin levels in tears and serum. RESULTS: Peak levels of 1.53 microg/ml (standard deviation [SD] +/- 0.94) and 0.15 microg/ml (SD +/- 0.04) were obtained at 12 hours in both tears and serum, gradually decreasing over 144 hours. All patients were disease-free by 6 months. CONCLUSIONS: Levels of azithromycin in patients with trachoma were found to be within minimum inhibitory concentration range for Chlamydia trachomatis (0.03-0.25 microg/ml) throughout the monitored period of 6 days.

Pharmacokinetic monitoring of anticancer drugs at King Faisal Specialist Hospital, Riyadh, Saudi Arabia.

Pharmacokinetic monitoring of anticancer agents has the potential to become of considerable clinical value. Recognizing this and the leading role of the King Faisal Specialist Hospital and Research Centre (KFSH & RC) in healthcare delivery in the Kingdom of Saudi Arabia, particularly in oncology, the authors have established a pharmacokinetics service and research laboratory equipped with the state-of-the-art analytical instrumentation. After the acquisition of these instruments, we initiated research work that lead to the development of improved analytical methods for methotrexate and 7-OH methotrexate (high-performance liquid chromatography [HPLC]), doxorubicin (HPLC), etoposide (HPLC), 5-fluorouracil (HPLC), mitoxantrone (HPLC), mesna and dimesna (HPLC), taxol (HPLC), aminoglutethimide (HPLC), tamoxifen (HPLC), and acrolein (HPLC), cisplatin or carboplatin (electrothermal atomic absorption spectrophotometry, ETAAS), cyclophosphamide (gas chromatography) and CCNU and BCNU (gas chromatography). Currently, most of these drugs are monitored selectively as requested by oncologists at the KFSH & RC. The authors are aware that controlled, randomized studies of the concentration-effect relationships for many of these drugs are still missing. However, the authors hope that once these studies become available, this service will be used more fully.

Pharmacokinetics of mesna and dimesna after simultaneous intravenous bolus and infusion administration in patients undergoing bone marrow transplantation.

This study was undertaken to examine the pharmacokinetics of mesna and its dimer form, dimesna, in the plasma and urine of patients undergoing bone marrow transplantation who received 130 mg/kg of mesna divided intravenously into a 30-mg/kg bolus dose followed immediately by 100 mg/kg infused over 12 hours for uroprotection. The relationship between and urinary excretion of mesna and dimesna also was examined by comparing the data obtained in patients who developed hemorrhagic cystitis versus those who did not. Blood and urine samples were collected at different time intervals after administration, and the plasma or urine was analyzed by liquid chromatography with electrochemical detection. Dimesna was analyzed in these samples after reduction back to mesna with sodium borohydride. The concentration-time data of mesna exhibited the characteristics of the two-compartment model well, and the mean +/-SD values of the distributive phase half-life (t1/2 alpha), postdistributive phase half-life (t1/2 beta), volume of distribution of the central compartment (Vdc), volume of distribution at steady state (Vdss), volume of distribution during the postdistributive phase (Vd beta), total clearance (Cl), and mean residence time (MRT) observed were 0.12 +/- 0.15 hours, 2.12 +/- 1.61 hours, 0.324 +/- 0.336 L/kg, 1.09 +/- 1.18 L/kg, 2.09 +/- 3.0 L/kg, 0.755 +/- 0.507 L/hr.kg, and 6.77 +/- 0.72 hours, respectively. The mean +/-SD values of t1/2 and MRT of dimesna were 1.29 +/- 0.6 hours and 6.68 +/- 1.05 hours, respectively, and the ratio of the area under the concentration-time curve (AUC) of mesna to that of dimesna was 1.21 +/- 0.57. The fractions of dose excreted in urine in the form of mesna and dimesna in 20 hours (fu) were 0.361 +/- 0.15 and 0.482 +/- 0.25, and the renal clearance (ClR) values were 0.244 +/- 0.201 L/hr.kg and 0.157 +/- 0.156 L/hr.kg, respectively. The urinary excretion of mesna in these patients was higher than that required for uroprotection for the whole duration of infusion, and there was no significant difference in the pharmacokinetics of mesna between patients who developed hemorrhagic cystitis and those who did not. This was not the case with dimesna, in which patients with hemorrhagic cystitis excreted in urine less than 50% of the amount of dimesna excreted by those without hemorrhagic cystitis.

Pharmacokinetics of oral fluconazole when used for prophylaxis in bone marrow transplant recipients.

The pharmacokinetics of fluconazole was investigated in 20 bone marrow transplant patients following oral administration of 200 mg of this drug. Blood samples were collected from each patient at different time intervals within 48 h after the first dose, and fluconazole was measured in plasma by high-performance liquid chromatography with UV detection. Urine was collected from 14 of these patients and analyzed similarly. The plasma concentration-time data exhibited the characteristics of the one-compartment model with first-order absorption quite well. The means +/- standard deviations of half-lives for absorption and elimination, peak concentration, time to peak, mean residence time, apparent volumes of distribution, area under the curve, and apparent oral clearance observed in these patients were 2.84 +/- 1.34 h, 19.94 +/- 18.7 h, 4.45 +/- 1.86 microg/ml, 8.34 +/- 5.97 h, 39.57 +/- 20.5 h, 0.874 +/- 0.48 liter/kg, 156.0 +/- 60.6 microg x h/ml, and 0.0256 +/- 0.0138 liter/h x kg, respectively. The amount of fluconazole excreted in urine in 24 h was 67.1 +/- 83 mg, which represents 33.55% +/- 41.6% of the dose administered. Patients who developed hemorrhagic cystitis excreted significantly (P < or = 0.0094) more fluconazole in 24 h than did those who did not.

Direct liquid chromatographic micro-measurement of tamoxifen in plasma of cancer patients.

We describe in this report a sensitive and direct method for the analysis of tamoxifen (TAM) in microsamples of plasma. The drug and internal standard (quinine bisulfate, I.S.) were separated on a 10-microm particle, 10 cm X 8 mm CN cartridge in conjunction with a radial compression system. The mobile phase was a mixture of 0.1 M sodium acetate in 0.001 M tetrabutylammonium phosphate solution (pH 6) and methanol (30:70, v/v) at a flow-rate of 4 ml/min. After addition of I.S. and o-phosphoric acid in acetonitrile (0.6 M) to the plasma (30 microl), the mixture was placed in an ultraviolet shortwave transluminator for 2 min prior to injection into the chromatograph. The compounds were detected in the effluent fluorometrically at excitation and emission wavelengths of 258 and 378 nm, respectively. Under these conditions, no interference in the assay from any endogenous substance or other concurrently used drugs was observed and the retention times of I.S. and TAM were 4.4 and 10.15 min, respectively. The concentration of TAM in plasma was linearly (r>0.9983) related to the peak height ratio (TAM/I.S.) in the range 0.01-2.0 microg ml(-1) and C.V. at 0.075, 0.4 and 1.2 microg ml(-1) was < or = 4.96%. We are currently using this assay for monitoring TAM in plasma and investigating its pharmacokinetics in cancer patients receiving cytotoxic drugs in addition to TAM as a multi-drug resistance modifier.

Effect of tamoxifen on the pharmacokinetics of doxorubicin in patients with non-Hodgkin's lymphoma.

The authors examined the effect of tamoxifen (TAM), a multiple-drug resistance modulator, on the pharmacokinetics of doxorubicin (DOX) in patients with non-Hodgkin's lymphoma treated according to the CHOP-protocol which included DOX, cyclophosphamide, vincristine, and prednisone. The dose of DOX was 50 mg/m2, but was reduced 25% if the patient was older than 60 years. Of these, 10 randomly-selected patients received a daily dose of 480 mg of TAM (Group-1) and 10 others did not (Group-2). Blood samples were collected at different time intervals, and DOX was measured in plasma by liquid chromatography. The concentration-time data of DOX exhibited the characteristics of the two-compartment open model well. The mean (SEM) values of alpha, beta, k12, k21, k10, Vc, Vss, AUC, total clearance, and mean residence time observed in Group-1 were 4.06 (0.96) hr(-1), 0.0395 (0.0068) hr(-1), 3.13 (0.79) hr(-1), 0.264 (0.052) hr(-1), 0.708 (0.19) hr(-1), 525 (156) l/m2, 1060 (163) l/m2, 1145 (234) microg x hr/l, 49.3 (8.5) l/hr x m2, and 26.8 (6.6) hours, respectively. Those in Group-2 were 4.99 (1.13) hr(-1), 0.0432 (0.0073) hr(-1), 2.46 (0.63) hr(-1), 0.111 (0.026) hr(-1), 2.46 (0.86) hr(-1), 231 (53) l/m2, 812 (149) l/m2, 1690 (276) microg x hr/l, 30.3 (4.1) l/hr x m2, and 29.7 (5.1) hours, respectively. Of these parameters, the difference between the two groups was significant (p < or = 0.0169) only in k21. Thus, the coadministration of TAM at the earlier-mentioned dose appears generally to have no significant influence on the pharmacokinetics of doxorubicin when used in the CHOP-protocol.

Effect of repeated dosing on the pharmacokinetics of oral fluconazole in bone marrow transplant patients.

We examined the pharmacokinetics of fluconazole in 11 bone marrow transplant patients after multiple oral daily dose of 200 mg of this drug. Blood was sampled at different intervals on day 1, day 13, and day 27. No dose was given on day 2, day 14, and day 28 to allow the concentration-time data to be collected over 48 hours. The 24 hour urine was also collected, and fluconazole was analyzed in both plasma and urine by a high performance liquid chromatography. The plasma concentration-time data were best described by the one-compartment model with first-order absorption. The overall inter-day change and the difference between day 1 and day 27 in the rate constant for absorption (ka), peak plasma concentration (Cmax), through plasma concentration (Cmin), time-to-peak (tmax), area-under-the-curve 0-24 (AUC0-24), rate constant for elimination (ka), mean residence time after oral administration (MRTor), and fraction of the dose excreted unchanged in urine 24 hours (fu24) were significant (P < or = 0.0029 and P < or = 0.01, respectively). However, the difference between day 1 and day 13 was significant (P < or = 0.05) only in ka, tmax, Cmax, Cmin, and AUC0-24, and between day 13 and day 27 was significant (P < or = 0.05) only in ka, Cmin, ka, and MRTor. There was no significant inter-day change in the renal clearance. The significant (P < or = 0.05) increases in Cmax, Cmin, and AUC0-24 after the dose given on day 13 as compared with day 1, and in Cmin on day 27 as compared with day 13 indicate that, in contrast to volunteers, the steady state condition was not reached on day 13 and possibly not on day 27 in these patients. This perhaps should be taken into account when prescribing fluconazole to seriously ill patients.

Microdetermination of propofol in plasma by a rapid and sensitive liquid chromatographic method.

A direct and sensitive liquid chromatographic method for the determination of propofol in 50 microliters of plasma is described. The separation of the drug and internal standard (methyldopa) was achieved using a 4 microns particle size C1R cartridge (10 cm x 8 mm i.d.) in conjunction with a radial compression system and a C18 precolumn module. The mobile phase consisted of 0.01 M sodium acetate solution (adjusted to pH 3 with acetic acid)-acetonitrile-methanol (37:47.25:15.75, v/v/v) at a flow rate of 2 ml min-1. The compounds were detected in the effluent spectrofluorimetrically with excitation and emission wavelengths of 276 and 310 nm, respectively. After the internal standard had been added, the sample was diluted with 50 microliters of hydrochloric acid and centrifuged prior to injection into the chromatograph. The peaks of both propofol and internal standard under these conditions were sharp and symmetrical, and the retention times were 8.2 and 5.15 min, respectively. The peak-height ratio (drug/internal standard) varied linearly (r > 0.9959) with concentration in the ranges 0.002-0.1 and 0.1-10 micrograms ml-1 and the relative standard deviation was consistently < 5.6%. There was no interference in the assay from the endogenous substance or other concomitantly used drug. This method is currently being used for monitoring propofol in intensive care patients and investigating its pharmacokinetics.

Urinary selenium in healthy and diabetic Saudi Arabians.

We examined Se in urine of 170 Saudi Arabian diabetics (19 insulin-dependent [type 1] and 151 insulin-independent [type 2]) and in an equal number of control subjects of the same origin by measuring the ratio of the concentration of this metal (C(Se)) to that of creatinine in urine (C(creat)) for each subject. The mean (and SEM) of C(Se) /C(creat) for the control subjects was 56 (2.9) mu mol/mol creat, whereas, the value for the diabetics combined or separated into type 1 and type 2 was 56.7 (3.2), 51.5 (6.3), and 57.4 (3.5) mu mol/mol creat, respectively. With the exception of type 2 diabetics who were treated with insulin in addition to oral hypoglycemic and diet (35 patients) (mean [SEM] = 43 (4.3) mu mol/mol creat), there was no significant difference in C(Se)/C(creat) between the diabetics and control subjects. Also, there was no significant correlation between C(Se)/C(creat) and age, sex, or weight of diabetics, whereas, the correlation with the degree of diabetic control was significant (p < 0.0136). Of all diabetes-associated disorders (cardiovascular diseases, neuropathy, ophthalmologic diseases, infections, and hepatic disease), only ophthalmologic diseases appears to cause a significant (p < 0.05) reduction in C(Se)/C(creat), but only among type 2 diabetics. Inasmuch as Se status is reflected by urinary Se, healthy Saudi Arabians appear to have Se status that is comparable or higher than those reported for other populations.

Pharmacokinetics of carboplatin in a patient with cervical cancer with ureteric obstruction before, during, and after hemodialysis.

The pharmacokinetics of total and free (ultrafilterable) platinum were investigated in a patient with cervical cancer with ureteric obstruction who, at the time of carboplatin administration, appeared to have a mild renal impairment (i.e., creatinine clearance 1 mL/s), but developed an acute renal failure shortly thereafter, which required hemodialysis. The decline in the concentration of total or free Pt in plasma as function of time correlated well (P < 0.0098) with that of serum creatinine concentration. The elimination half-lives (t1/2) of total and free Pt in this patient were eight- and nine-fold longer than those observed earlier for patients with normal renal function, and the total body clearance was 12.4% and 18.4%, respectively. Although t1/2 of Pt during dialysis was two to three times (total Pt) and eight times (free Pt) shorter than those observed before and after dialysis, three sessions of hemodialysis removed only 5.6% of total Pt and 9.3% of free Pt. Because the pre- and post-dialysis t1/2 values were similar, hemodialysis apparently had no impact on the intrinsic elimination of Pt in this patient.