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.

Steady-state kinetics of doxepin and imipramine in Saudi patients with interethnic comparison.

The pharmacokinetics of doxepin (DX) was studied in 21 Saudi patients treated long term with oral doses of this tricyclic antidepressant agent. The mean (SEM) values of the dose-normalized steady-state concentration and the apparent clearance after oral administration of this drug were 25.8 (4.8) ng.ml-1/mg.kg-1 and 2.529 (0.342) 1.h-1.kg-1, respectively. The pharmacokinetics of imipramine (IMI) was also studied in 30 Saudi patients who received oral doses of this drug for long durations. The mean dose-normalized steady-state concentration of IMI was 68.3 (19.7) ng.ml-1/mg.kg-1, and the mean apparent clearance after oral administration of IMI was 1.619 (0.353) 1.h-1. kg-1. The mean (SEM) ratio of the steady-state concentration of the metabolite desipramine (DES) to that of IMI (DES/IMI) was 0.873 (0.151). Using this value and the ratio of the mean apparent clearance after oral administration (TCL) of DES to that of IMI, the fraction of IMI metabolized to DES was calculated to be 0.489. The TCL of DES was estimated from data obtained for three additional patients who received oral doses of this drug for long durations. A mean value of 0.907 (0.351) 1.h-1.kg-1 was obtained.

Endotoxemia and release of tumor necrosis factor and interleukin 1 alpha in acute heatstroke.

To determine whether endotoxemia and release of tumor necrosis factor (TNF-alpha) and/or interleukin 1 alpha (IL-1 alpha) are involved in the pathogenesis of heatstroke, 17 adult patients with a mean rectal temperature of 42.1 +/- 0.2 degrees C were studied. Blood samples were taken on admission and after cooling was completed. TNF-alpha and IL-1 alpha levels were measured by enzyme-linked immunosorbent assay, and lipopolysaccharide (LPS) content was measured by the chromogenic substrate modification of the Limulus amebocyte lysate. TNF-alpha, IL-1 alpha, and LPS were elevated in all patients [199 +/- 25 (SE) pg/ml, 480.5 +/- 68.3 pg/ml, and 8.60 +/- 1.19 ng/ml, respectively, compared with normal control values of 31.4 +/- 8.4 pg/ml, 53.7 +/- 5.32 pg/ml, and less than 9 pg/ml]. There was no significant correlation between temperature and the circulating concentration of TNF-alpha, IL-1 alpha, and LPS. Postcooling TNF-alpha, IL-1 alpha, and LPS concentrations were significantly decreased but still above normal control values. The findings suggest that these mediators may have a role in the pathogenesis of heatstroke that could change the strategy of management.

Mechanisms of hypophosphatemia in humans with heatstroke.

Hypophosphatemia is common in heatstroke, but little is known about its mechanism. We investigated 10 consecutive patients with heatstroke (mean age 58 +/- 2 yr) whose mean rectal temperature at admission was 42.3 +/- 0.2 degrees C. Eight patients presented with hypophosphatemia [0.48 +/- 0.08 mmol/l, normal range (NR) 0.8-1.4 mmol/l], associated with increased fractional excretion of phosphate (19.8 +/- 6.4%, NR 6-20%) relative to plasma phosphate levels and reduced renal threshold for phosphate (0.55 +/- 0.08 mmol/l glomerular filtrate, NR 0.8-1.4 mmol/l). Plasma parathyroid hormone (75.0 +/- 5 pmol/l) and calcium (2.24 +/- 0.02 mmol/l) levels and fractional excretion of calcium were normal (1.66 +/- 0.27%). There was no evidence of uricosuria or aminoaciduria, and only one patient had glucosuria. Arterial carbon dioxide was decreased in eight patients (28 +/- 1.1 Torr); however, none had elevated blood pH (7.35 +/- 0.02). The results suggest that heatstroke-related hypophosphatemia is associated with abnormal phosphaturia independent of the parathyroid hormone level, and there is no evidence of tubular dysfunction.

Pharmacokinetics of azathioprine after repeated oral and single intravenous administration.

The pharmacokinetics of azathioprine (AZN) were examined in 28 renal transplant patients treated orally with 25 to 150 mg AZN once daily in combination with cyclosporin A and prednisone, and after single intravenous (IV) injection of 5 mg/kg AZN using the rabbit as an in vivo model. The steady-state concentrations of AZN observed in these patients ranged from 6 to 583 micrograms/L, and the interday coefficients of variation of the concentration in three randomly selected patients were 38%, 12%, and 4.6%. The frequency distribution pattern of the apparent oral clearance (TCLor) of AZN separates the patients almost equally into poor (TCLor = 0.126 to 4 L/hour.kg) and extensive metabolizers (TCLor = 5 to 12 L/hour.kg). The data obtained from the IV administration displayed the two-compartment model characteristics with mean (standard error of the mean) of alpha, beta, Vc, and total body clearance of 15.3 (2)/hour, 2.38 (.64)/hour, 1.05 (.3) L/kg, and 8.12 (1.26) L/hour.kg, respectively. The large variability in the pharmacokinetic parameters of AZN in patients and even in rabbits under carefully controlled conditions that may be ascribed to the complexity of its metabolism necessitates a careful approach to its dose selection.

Acetylator phenotypes of Saudi Arabians by a simplified caffeine metabolites test.

The authors examined acetylator phenotypes of 296 Saudi subjects of Arabic origin by measuring the molar concentration ratio of two caffeine metabolites, 5-acetylamino-6-formylamino-3-methyluracil (AFMU) and 1-methylxanthine (1MX), using a simplified version of a previously reported high-performance liquid chromatographic method. Spot urine samples were collected from the subjects who regularly drink coffee, tea, or other caffeinated beverages. The subjects were originally from different regions of Saudi Arabia but currently live primarily in the capital city of Riyadh. The day-to-day reproducibility of the molar concentration ratio of AFMU/1MX was established in 14 randomly selected subjects. These metabolites were stable in urine at 4 degrees and -20 degrees, but AFMU was unstable at room temperature (23 degrees). The frequency distribution data indicate that 72.3% of the subjects are of slow acetylator phenotype.

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.

Steady state pharmacokinetics of propranolol in Saudi Arabian patients and comparison with data for different populations.

The steady state pharmacokinetics of propranolol was examined in 48 Saudi Arabian patients chronically treated with oral doses [mean (SEM) = 85.8 (5) mg] of this drug. The mean (SEM) of the steady state concentration (Css) per mg/kg daily dose was 21.8 (3.1) ng.ml-1/mg.kg-1. A 6-fold variability in Css was observed between patients treated with 40 mg every 8 hours and 14-fold between patients treated with 40 mg twice daily. The frequency distribution of the apparent oral clearance (TCLor) of propranolol was bimodal with 88% of the patients showing TCLor of 18 to 372 l.hr-1 while the remainder had TCLor of 471 to 749 l.hr-1. The mean (SEM) of the TCLor per kg body weight for all 48 patients was 3.16 (0.38) l.hr-1.kg-1. Both Css and TCLor obtained for Saudi Arabian patients are not significantly different from those reported for subjects from Western populations. While Css increased proportionally (P less than .001) with dosing, a near-significant (P less than .06), inverse, linear relationship was found between age and TCLor. No significant effect of sex, body weight, or disease state (i.e., heart diseases, hypertension, depression, migraine) on Css or TCLor was detected.

N-acetylation polymorphism and diabetes mellitus among Saudi Arabians.

The acetylator phenotypes of 200 Saudi diabetics and an equal number of control subjects of the same origin were determined by measuring the peak height ratio of two urinary caffeine metabolites, 5-acetylamino-6-formylamino-3-methyluracil (AFMU) and 1-methylxanthine (1MX), using a simplified high-performance liquid chromatographic method. Urine samples were collected from the diabetics and the control subjects who regularly drink coffee, tea, or caffeinated beverages as part of their normal daily diet. The patients were classified as either type 1 (insulin-dependent) (28 patients) or type 2 (insulin-independent) diabetics (172 patients) according to standard criteria. The reproducibility of acetylator phenotype was established by examining the peak height ratio of AFMU/1MX in 18 diabetics and 6 control subjects on different days. Significant differences in the proportion of rapid acetylators were observed between type 1 (53.6%) and type 2 (33.7%) diabetics (P < or = .0436), and between the control group (26%) and the overall diabetics (36.5%) (P < or = .024) or those with type 1 disease (P < or = .0028). Also, there was a significant (P < or = .0436) association between rapid acetylator status and type 1 diabetes mellitus.

Steady-state kinetics of fluoxetine and amitriptyline in patients treated with a combination of these drugs as compared with those treated with amitriptyline alone.

The steady-state kinetics of amitriptyline (AMI), fluoxetine (FLU), and their active metabolites nortriptyline (NTRIP) and norfluoxetine (NFLU) were studied in 15 patients treated once daily for long durations with 50 mg of AMI and 20 mg of FLU. These compounds were analyzed simultaneously in plasma by liquid chromatography. The means and (SEM) of the steady-state concentrations (Css) of AMI, NTRIP, FLU, and NFLU were 80.6 (14.2), 52.6 (10.3), 85.3 (16.1), and 90 (13.6) ng/mL, respectively, and the apparent oral clearances (CLor) of AMI and FLU were 42.4 (8.6) and 14.9 (2.5) L/hr, respectively. The metabolite/drug steady-state concentration ratio (Css(m)/Css) for NTRIP/AMI was 0.75 (0.14) and for NFLU/FLU was 1.27 (0.17). There was a significant correlation (P < 0.05) between Css of FLU and that of AMI or NTRIP. The Css and Css(m)/Css values obtained for AMI were higher (P < 0.056 and P < 0.0034, respectively) than those we observed in 10 patients treated solely with the same dose of AMI. The twofold increase in Css of AMI and ninefold increase in Css of NTRIP seem to be the result of inhibition of the metabolism of these compounds by FLU, particularly the ring hydroxylation. Norfluoxetine may have a small inhibitory influence on the metabolism of NTRIP but lacks this effect on the metabolism of AMI.

Impaired elimination of atenolol in a nephropathic patient with self-medication overdose.

A case of intoxication with atenolol (plasma concentration of 2.71 mg/L) caused by an improper self-medication combined with impaired renal function is presented. The patient was supported with atropine, isoproterenol, dopamine, and dobutamine, and a thorough pharmacokinetic monitoring of atenolol was conducted. As the serum creatinine concentration returned slowly to baseline with good diuresis, the concentration of atenolol decreased (biologic half-life = 2.95 days) and the blood pressure gradually recovered. The patient improved and was subsequently discharged in good health. Had pharmacokinetic monitoring of atenolol not been performed, hemodialysis would have been indicated.

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.

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.

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.

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.

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.

Relationship between antipyrine metabolism and acetylation phenotype in health and chronic liver diseases.

The authors examined the activity of N-acetyltransferase and that of microsomal P-450 isoenzymes in health and hepatic disease state by determining the acetylation phenotype and the total (CLAP) and metabolic clearances of antipyrine to form norantipyrine or N-demethylantipyrine (MCLnora), 3-hydroxymethylantipyrine (MCLhma), and 4-hydroxyantipyrine (MCLha) in 21 healthy subjects and in 33 patients with chronic liver diseases (CLD) and investigated the relationship between the activities of these two enzyme systems. The acetylation phenotype was determined according to the urinary caffeine metabolites test. The mean and (SEM) of CLAP, MCLhma, MCLha, and MCLnora in healthy subjects were 2.42 (0.264), 0.193 (0.031), 0.322 (0.045), and 0.288 (0.04) L/h, and those observed in patients with CLD were 0.98 (0.1), 0.076 (0.015), 0.131 (0.026), 0.103 (0.022) L/h, respectively. The prevalence of fast acetylation among the healthy subjects and patients with CLD was 38% and 39%, respectively. Although all metabolic clearances appear to be reduced in healthy slow acetylators, the reduction was only significant in MCLnora, indicating a direct association between the activity of N-acetyltransferase and that of P-450 IIIA3 responsible for the N-demethylation of antipyrine. Conversely, slow acetylators with CLD exhibited significantly higher CLAP and near-significantly larger metabolic clearances including MCLnora, which suggests that P-450 activity in fast acetylators is more sensitive to chronic liver diseases than in slow acetylators.

Simple methods for estimating percent disintegrated--time data.

Two techniques are described for the treatment of dissolution rates to estimate the percent disintegrated--time data for tablets and capsules. The first is an extension of an equation derived previously with the assumption of first-order disintegration and dissolution processes; whereas, the second involves the determination of the rate constant from the terminal segment of the curve and the use of numerical derivatives according to a disintegration kinetics-independent approach. The dissolution data of six commercial tablet and capsule formulations were treated according to the described techniques. Good agreement was found between the percent disintegrated--time data estimated by the second approach for an acetaminophen tablet and those obtained by a well-established model where a Weibull function was employed.

Disintegration-dissolution analysis of percent dissolved-time data.

A simple, graphical method is described for the disintegration--dissolution analysis of cumulative percent dissolved--time data. The technique is based on a biexponential equation with the assumption of first-order disintegration and dissolution according to a simple dissolution model. The dissolution data obtained for six commercial tablets and capsules adequately fit the developed equation. The described method is simple and can handle initial data points that are usually ignored by other techniques.