Pharmacokinetic and pharmacodynamic differences between two low dosages of aspirin may affect therapeutic outcomes

BACKGROUND: Meta-analyses of the prevention of major vascular events by aspirin suggest therapeutic equivalence of all dosages. However, the optimal dosage still remains problematic, and a recent trial found aspirin 160 mg/day to be more effective than 80 mg/day for secondary prevention of ischaemic stroke. OBJECTIVE: To evaluate two low dosages of aspirin in terms of pharmacokinetics and pharmacodynamics (inhibition of platelet thromboxane generation and urinary excretion of thromboxane and prostacyclin metabolites). DESIGN AND PARTICIPANTS: A randomised cross-over study was performed in 16 healthy volunteers (9 women and 7 men, 33.8 +/- 5.1 years old) given enteric-coated aspirin 80 or 160 mg/day for 7 days. METHODS: Plasma concentrations of salicylate and aspirin were measured by high-performance liquid chromatography (HPLC) after both the first and the last dose (days 1 and 7). The usual pharmacokinetic parameters were then derived. Serum thromboxane B2 (TxB2) was measured by radioimmunoassay. The urinary excretion of 11-dehydro-TxB2 and 2,3-dinor-6-keto-prostaglandin F1alpha were measured on 8-hour urine samples by immunoassay after extraction and HPLC separation, both before and after 7 days of drug administration. RESULTS: With the 160 mg dosage, but not with the 80 mg dosage, higher concentrations of aspirin were found at day 7 compared with day 1. For aspirin 80 mg/day, 24-hour area under the concentration-time curve (AUC24) was similar on days 1 and 7 (569 +/- 339 vs 605 +/- 377 microg. h/L), but increased from 904 +/- 356 microg. h/L on day 1 to 1355 +/- 883 microg. h/L on day 7 with the higher dosage. Similarly, the AUC24 for salicylate was similar on days 1 and 7 with the lower dosage, but significantly increased from day 1 to day 7 after the higher dosage. This paralleled inhibition of serum TxB2 levels (99% vs 95% average inhibition by 160 and 80 mg/day) and of urinary excretion of thromboxane metabolite (77% vs 61% average inhibition by 160 and 80 mg/day), without altering the excretion of prostacyclin metabolite.Conclusions: Inhibition of serum TxB2 generation and of thromboxane metabolite urinary excretion by the lower dosage of aspirin, although substantial, still appeared incomplete. The small but significant further increase of serum TxB2 inhibition by the higher dosage was accompanied by an even greater inhibition of urinary excretion. We suggest that in some instances this difference would translate into a greater clinical benefit with the higher aspirin dosage. Our findings may also contribute to better definition of the recent concept of 'aspirin resistance'.     

Effect of additive selection on calculated aluminum content of parenteral nutrient solutions.

PURPOSE: The quantity of aluminum in common ingredients used to compound parenteral nutrient (PN) solutions was calculated to quantify the actual aluminum content, and opportunities to modify the aluminum content by changing the manufacturer of the ingredients were explored. METHODS: A retrospective evaluation of a random sample of 10 neonatal, 10 pediatric, and 10 adult patients who received PN solutions was performed to quantify the aluminum content in these solutions on the basis of the ingredients used at the authors' institution. A recalculation was performed using the lowest aluminumcontaining ingredients to determine the potential for aluminum minimization in each PN solution. RESULTS: Various manufacturers produce each ingredient required to make PN solutions. Significant variation exists among manufacturers, vial size, and concentrations. Statistically significant differences in the mean aluminum content of PN solutions before and after aluminum minimization were found to exist within each sample of patients. Among the neonatal PN solutions, aluminum content was significantly reduced from a mean +/- S.D. of 84.16 +/- 47.61 to 33.6 +/- 16.69 mug/kg/day. The pediatric PN solutions had a significant decline in aluminum content from a mean +/- S.D. of 16.24 +/- 3.66 to 6.84 +/- 2.66 mug/kg/day. Aluminum content in the high-risk adult PN solutions significantly decreased from a mean +/- S.D. of 4.58 +/- 2.06 to 2.31 +/- 0.63 mug/kg/day. CONCLUSION: There is wide variability in the aluminum concentration of injectable products used in the compounding of PN solutions. Selecting products with low aluminum concentration may substantially reduce the amount of the element administered to patients.     

Plasma gabapentin concentrations in children with epilepsy: influence of age,relationship with dosage,and preliminary observations on correlation with clinical response

The influence of age and administered daily dosage on the plasma concentrations of gabapentin (GBP) at steady state was evaluated in a group of 41 children and young adults (aged 3-30 years) receiving long-term adjunctive treatment with GBP for the management of refractory partial-onset seizures. For each patient, peak and trough concentrations were determined by a specific high-performance liquid chromatography (HPLC) method in samples obtained before the morning dose and 2.5 hours later, respectively. To assess within-subject relationship between plasma concentration and dosage, 30 patients were evaluated at more than one dosage level. Within the assessed dose range, plasma GBP concentrations were linearly related to dose. Apparent oral clearance values (mean +/- SD) in children aged 6 years or less (4.8 +/- 0.9 mL/kg/min) were comparable with those observed in children aged 7 to 15 years (4.6 + 1.5 mL/kg/min) and moderately higher than those found in young adults (3.9 + 0.9 mL/kg/min), even though differences among groups failed to reach statistical significance. There was, however, a significant difference in CL/F between children aged 10 years or less and older children (5.1 +/- 1.1 vs. 3.8 +/- 1.2 mL/kg/min, P < 0.005). Of the 41 patients who entered the study, 22 discontinued treatment, mostly due to insufficient efficacy. No significant difference in plasma GBP concentration was detected between patients showing a greater than 50% reduction in seizure frequency (4.1 +/- 1.9 microg/mL, n = 11, mean +/- SD) and those having no significant clinical improvement (4.4 +/- 1.7 microg/mL, n = 30). These results indicate that in children given dosages up to 50 mg/kg/d (mean, 25 mg/kg/d), GBP pharmacokinetic analyses show no important deviation from linearity. The data also suggest that, on average, children may need moderately higher dosages to reach plasma GBP concentrations comparable with those found in adults. There seems to be a large variation in the plasma concentrations of the drug associated with a favorable therapeutic response.     

Absence of effect of stimulants on the phamacokinetics of desipramine in children.

We conducted a retrospective chart review to examine the pharmacokinetic interaction between desipramine and the stimulants methylphenidate and dexedrine using routinely monitored desipramine serum concentrations in children receiving desipramine either alone or with a stimulant. Subjects were 142 children and adolescents (age 6-17 yrs; 113 taking desipramine, 29 taking desipramine-stimulants) in whom 401 dose- and weight-normalized serum concentrations were evaluated (333 desipramine, 68 desipramine-stimulants). Desipramine pharmacokinetic parameters were similar for both groups, including mean weight-corrected dose (3.66+/-1.36 mg/kg, desipramine; 3.66+/-1.09 mg/kg, desipramine-stimulants; p=0.97), weight- and dose-normalized serum concentrations (47.26+/-39.26 [microg/L]/[mg/kg], desipramine, 39.02+/-19.92 [microg/L]/[mg/kg], desipramine-stimulants; p=0.09), and clearance (0.690+/-0.913 [L/kg]/hr, desipramine; 0.613+/-0.514 [L/kg]/hr, desipramine-stimulants; p=0.499). When stratified by age, gender, and type of stimulant, no difference was detected (p>0.05) between groups. Our findings indicate the absence of a clinically significant interaction between desipramine and stimulants.     

Dosage of beta-adrenergic blockers after myocardial infarction.

Dosages of beta-adrenergic blockers prescribed after myocardial infarction (MI) in a Veterans Affairs medical center were reviewed to determine if dosages were adjusted to target dosages used in clinical trials. The medical records of all patients with a discharge diagnosis of MI were reviewed. The target dosage, selected from major clinical trials, was atenolol 100 mg/day p.o., metoprolol tartrate 200 mg/day p.o., or propranolol 180-240 mg/day p.o. A systolic blood pressure of < or = 100 mm Hg and pulse rate of < or = 50 beats/min were defined as the clinical markers of the maximum tolerated beta-blocker dosage. A discharge diagnosis of MI was identified in 396 patients between January 1999 and December 2000, and 106 patients met the inclusion criteria. The patients had a mean +/- S.D. age of 66.3 +/- 10.7 years, 98% were men, and all received either atenolol or metoprolol. The mean +/- S.D. systolic and diastolic blood pressure and pulse rate on admission were 135 +/- 30 and 75 +/- 18 mm Hg and 80 +/- 20 beats/min, respectively. The mean +/- S.D. dosages for atenolol and metoprolol were 54 +/- 39 and 90 +/- 77 mg/day at the time of discharge, 54 +/- 38 and 95 +/- 81 mg/day at 6 months after discharge, and 53 +/- 40 and 82 +/- 80 mg/day at 12 months, respectively. Only 15% of the patients reached the target dosage, as defined in clinical trials, of a beta-blocker. No reason for maintaining the beta-blocker dosage was documented for 65% of the patients. Beta-blockers were prescribed frequently after MI but usually were not used at dosages that matched those in clinical trials.     

Acute potassium dichromate poisoning: a toxicokinetic case study

CASE REPORT: A 48-year-old man drank 150 mL of an aqueous solution containing potassium dichromate 22.5 g in a suicidal attempt and was admitted 7 hours after the ingestion. Hemodialysis was promptly undertaken and chromium concentrations in serum, erythrocytes, and dialysate were determined during the treatment. Chromium elimination in urine was monitored during hemodialysis and the subsequent 400 hours. The total chromium eliminated via hemodialysis and urine was calculated as 36.7 mg or 0.16% of the ingested dose. Spontaneous urinary elimination proceeded according to an open one-compartment model. The elimination half-life was 71.37 hours +/- 17.13 hours (95% CI). Chromium elimination from serum followed an open two-compartment model, with the half-lives of 3.16 hours +/- 2.63 hours for phase 1 and 50 hours +/- 27 hours (95% CI) for phase 2. Calcium-EDTA therapy had no influence on erythrocyte, serum, or urine chromium level. It contributed, however, to a significant increase in chromium elimination rate in the dialysate. Serum zinc was very low at admission and serum zinc, copper, and magnesium were controlled during the initial 30 hours.     

Serum level monitoring of a new slow release theophylline formulation in patients with chronic lung disease.

1 Serum theophylline levels were performed in 26 patients with chronic lung disease receiving rapid release theophylline (125 mg 6 hourly) and 28 patients receiving slow release theophylline (250 mg 12 hourly) under steady state conditions. 2 For rapid release theophylline the mean +/- s.d. serum theophylline levels at 0 and 2 h were 41.0 +/- 21.7 and 52.3 +/- 20.9 mumol l-1 respectively and for slow release theophylline at 0, 4 and 6 h 43.7 +/- 25.5, 50.9 +/- 23.0 and 51.7 +/- 26.4 mumol l-1 respectively. 3 Serum theophylline monitoring with slow release theophylline was performed in 70 patients with chronic lung disease. The initial dose was 250 mg administered 12 hourly. 4 The mean +/- s.d. steady state serum theophylline level achieved was 76.0 +/- 18.8 mumol l-1 and the mean +/- s.d. dose to produce this level was 9.4 +/ 2.3 mg kg-1 day-1. There was no correlation between dosage and serum theophylline level. 5 Sixty percent of patients required a dosage change for stabilization (375 to 1000 mg/day). Seventeen patients reported unwanted effects (nausea or tremor), which either settled quickly or resolved with dosage reduction. 6 Serum theophylline levels were obtained at different dosages in 44 patients and 18 patients demonstrated dose-dependent kinetics. 7 An initial dose of 500 mg/day is recommended and dosage increments should not exceed 125 mg/day with monitoring by serum theophylline levels.     

Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence

Methadone is widely used for the treatment of opioid dependence. Although in most countries the drug is administered as a racemic mixture of (R)- and (S)- methadone, (R)-methadone accounts for most, if not all, of the opioid effects. Methadone can be detected in the blood 15-45 minutes after oral administration, with peak plasma concentration at 2.5-4 hours. Methadone has a mean bioavailability of around 75% (range 36-100%). Methadone is highly bound to plasma proteins, in particular to alpha(1)-acid glycoprotein. Its mean free fraction is around 13%, with a 4-fold interindividual variation. Its volume of distribution is about 4 L/kg (range 2-13 L/kg). The elimination of methadone is mediated by biotransformation, followed by renal and faecal excretion. Total body clearance is about 0.095 L/min, with wide interindividual variation (range 0.02-2 L/min). Plasma concentrations of methadone decrease in a biexponential manner, with a mean value of around 22 hours (range 5-130 hours) for elimination half-life. For the active (R)-enantiomer, mean values of around 40 hours have been determined. Cytochrome P450 (CYP) 3A4 and to a lesser extent 2D6 are probably the main isoforms involved in methadone metabolism. Rifampicin (rifampin), phenobarbital, phenytoin, carbamazepine, nevirapine, and efavirenz decrease methadone blood concentrations, probably by induction of CYP3A4 activity, which can result in severe withdrawal symptoms. Inhibitors of CYP3A4, such as fluconazole, and of CYP2D6, such as paroxetine, increase methadone blood concentrations. There is an up to 17-fold interindividual variation of methadone blood concentration for a given dosage, and interindividual variability of CYP enzymes accounts for a large part of this variation. Since methadone probably also displays large interindividual variability in its pharmacodynamics, methadone treatment must be individually adapted to each patient. Because of the high morbidity and mortality associated with opioid dependence, it is of major importance that methadone is used at an effective dosage in maintenance treatment: at least 60 mg/day, but typically 80-100 mg/day. Recent studies also show that a subset of patients might benefit from methadone dosages larger than 100 mg/day, many of them because of high clearance. In clinical management, medical evaluation of objective signs and subjective symptoms is sufficient for dosage titration in most patients. However, therapeutic drug monitoring can be useful in particular situations. In the case of non-response trough plasma concentrations of 400 microg/L for (R,S)-methadone or 250 microg/L for (R)-methadone might be used as target values.     

Effect of low-dose troleandomycin on theophylline clearance: implications for therapeutic drug monitoring.

Troleandomycin (TAO) is an alternative agent used in the treatment of severe, steroid-requiring asthma. Its mechanism of action, once thought to be inhibition of theophylline clearance, remains unclear. Twenty-four-hour theophylline profiles were obtained in 11 children with severe asthma prior to and after 2 and 12 weeks of low-dose TAO therapy. Theophylline dosages were adjusted by blinded investigators to maintain serum theophylline concentrations (STCs) between 10 and 20 micrograms/ml. Dosages were decreased from 877 +/- 60 mg/day (mean +/- SEM) before TAO to 811 +/- 56 mg/day (NS) after 2 weeks and 764 +/- 56 mg/day (p less than 0.05) after 12 weeks. Because of the dosage adjustments, STCs did not increase significantly. Theophylline clearance was reduced from 65.7 +/- 9.8 ml/kg/hour at baseline to 50.2 +/- 4.1 ml/kg/hour (p less than 0.05) after 2 weeks and 50.1 +/- 6.2 ml/kg/hour (p less than 0.05) after 12 weeks of TAO therapy. We conclude that TAO can significantly reduce theophylline clearance, resulting in increased STCs if dosages are not titrated. We recommend an empiric 25% reduction of daily theophylline dose with the initiation of TAO. We also recommend monitoring STCs 4 hours after the morning dose (with twice-daily dosing of sustained-release products) after 3, 7, 14, and 30 days of TAO therapy, then periodically as indicated.     

Determination of arsenic in urine by atomic absorption spectrophotometry for biological monitoring of occupational exposure to arsenic.

An atomic absorption spectrophotometric (AAS) method was successfully applied to analysis of urine for arsenic (As) as a measure of biological monitoring of occupational exposure to As in Vietnam. The application of the method to urine samples from 75 non-exposed control urbanites (after 2-day abstinence from sea foods) gave a reference level of 62.4 +/- 11.6 microg/l (as mean +/- S.D.), from which the upper limit of the normal value (74 microg/l as mean +/- 1 S.D.) and the acceptable limit (100 microg/l as mean +/- 3S.D.) were deduced. Further application to urine samples from 147 workers occupationally exposed to As in Bacthai Non-ferrous Metallurgic Corporation showed significantly elevated levels of As in urine, with mean +/- S.D. of 78.5 +/- 20.2 microg/l. Improvement of working conditions to reduce As exposure resulted in substantial reduction in the ratio of those with urinary As at the level in excess of the acceptable limit. The practical importance of total arsenic determination in urine after 2-day sea food abstinence is discussed in connection with current conditions in analytical laboratories in Vietnam.     

Changes in serum alpha2u-globulin levels in castrated male rats treated with testosterone propionate in a Hershberger assay

The Hershberger assay has been proposed as a candidate screening test method for the detection of androgenic and anti-androgenic chemicals and is being validated presently under the test guideline programme of the Organization for Economic Cooperation and Development (OECD). Rat alpha2u-globulin is male rat-specific protein appearing in their serum and urine, and the protein is known to be induced by androgens. We investigated the usefulness of measuring serum alpha2u-globulin levels as a parameter for the androgenic activity of chemicals tested in the Hershberger assay. The serum alpha2u-globulin level was measured after the administration of testosterone propionate at dosages of 0, 20, 100 or 500 microg kg(-1) day(-1) for ten consecutive days in the castrated male rats. The ventral prostate, balbocavernosus/levator ani muscles, glans penis and Cowper's gland were collected and weighed. Although all the androgen-responsive organ weights were increased significantly at dosages of 100 and 500 microg kg(-1) day(-1), the serum alpha2u-globulin level was increased significantly only at a dosage of 500 microg kg(-1) day(-1). These results show that the serum alpha2u-globulin level may be a useful biomarker for detecting androgenic activity caused by test chemicals, but it is less sensitive than the organ weights of androgen-responsive tissues in the Hershberger assay.     

Octreotide and Potassium Homeostasis

Somatostatin infusion causes hyperkalemia in healthy subjects and in some animal models. The purpose of this investigation was to determine what effect octreotide has on potassium homeostasis during serious illness and if there is a dose-response relationship. Sixty-six male Sprague-Dawley rats (185–225 g) were randomized to receive parenteral nutrition (PN) only, PN plus continuous infusion of Escherichia coli lipopolysaccharide (LPS), or PN plus LPS plus octreotide 10, 100, or 1000 μg/kg/day for 48 hours. Before randomization all animals received isocaloric, isonitrogenous, isokalemic PN. A 24-hour urine was collected and a blood sample was taken at the end of the study immediately before euthanization. Data were analyzed by ANOVA and Duncan's multiple range test. Nonhemolyzed serum samples from 50 rats were available for study. Serum potassium concentrations were in the normal range for rats and did not differ significantly among the groups: 5.97 ± 0.86, 5.96 ± 1.58, 5.78 ± 1.48, 5.79 ± 1.67, 5.35 ± 0.78 mEq/L, respectively. No differences among groups were found for fractional excretion of potassium or serum creatinine concentration. Octreotide administration in escalating dosages does not cause hyperkalemia in endotoxemic rats given intravenous potassium at a constant rate by PN.     

Pharmacokinetics of perfluorooctanoate in cynomolgus monkeys.

The pharmacokinetics of perfluorooctanoate (PFOA) in cynomolgus monkeys were studied in a six-month oral capsule dosing study of ammonium perfluorooctanoate (APFO) and in a single-dose iv study. In the oral study, samples of serum, urine, and feces were collected every two weeks from monkeys given daily doses of either 0, 3, 10, or 20 mg APFO/kg. Steady-state was reached within four weeks in serum, urine, and feces. Serum PFOA followed first-order elimination kinetics after the last dose, with a half-life of approximately 20 days. Urine was the primary elimination route. Mean serum PFOA concentrations at steady state in the 3, 10, and 20 mg/kg-day dose groups, respectively, were 81, 99, and 156 microg/ml in serum; 53, 166, and 181 microg/ml in urine; and, 7, 28, and 50 microg/g in feces. Mean liver concentrations reached 16, 14, and 50 microg/g in the 3, 10, and 20 mg/kg groups, respectively. In the iv study, three monkeys per sex were given a single dose of 10 mg/kg potassium PFOA. Samples were collected through 123 days. The terminal half-life of PFOA in serum was 13.6, 13.7, and 35.3 days in the three male monkeys and 26.8, 29.3, and 41.7 days in the three females. Volume of distribution at steady state was 181 +/- 12 and 198 +/- 69 ml/kg for males and females, respectively. Based on the result of both the oral and iv studies, the elimination half-life is approximately 14-42 days, and urine is the primary route of excretion.     

Pharmacokinetics of vancomycin administered as prophylaxis before cardiac surgery

Vancomycin concentrations in serum, tissues, and sternum, administered as prophylaxis to patients during coronary artery bypass surgery, were measured. Vancomycin (15 mg/kg) was administered to 15 patients 1 hour before skin incision. Blood, tissue, and sternum samples were collected before, during, and after bypass. The concentration in serum at the end of infusion was 55.1 +/- 22.8 microg/mL, the mean elimination half-life was 9 +/- 4 hours, the areas under the concentration-time curve (AUC) from 0 to 12 hours and from 0 to infinity were 90.6 +/- 25.1 and 289.7 +/- 86.5 microg/h per mL, respectively, the mean residence time (MRT) was 11.9 +/- 5.0 hours, the mean volume of distribution was 51.1 +/- 12.2 L, and the total clearance was 78.3 +/- 32.6 mL/min. Vancomycin concentrations in serum, tissues, and sternum during the operation were greater than the MIC90 for most staphylococci and ranged from 16 to 55 microg/mL in serum and from 4 to 39 microg/g in sternum and tissues.     

Sulfadiazine versus sulfafurazole excretion in urine and risk of crystallization in children with conventional dosage regimen

The excretion of sulfadiazine (Adiazin) (n = 8) and sulfafurazole (n = 8) in urine and the risk of crystallization were compared in children, 3-14 years of age. They suffered from acute urinary tract infection and were treated with conventional dosage regimen of either of the sulfonamides. Sulfadiazine (4 mg/kg twice daily, the initial dose 8 mg/kg) produced active serum drug levels which in relation to antimicrobial activity of sulphonamides corresponded to 25-30% of those obtained with sulfafurazole (50 mg/kg four times a day). In urine the corresponding sulfadiazine levels were 21-61% of those of sulfafurazole. In none of the urine fractions sulfadiazine concentrations exceeded the theoretical drug solubility but sulfafurazole exceeded this risk limit altogether in 4 urine fractions (2 patients). Urine sediment showed, however, sulfonamide crystals in only one urine fraction of the sulfafurazole group. The results suggest that with conventional dosage regimen sulfafurazole produces higher effective serum and urine drug concentrations in children than sulfadiazine but shows a higher risk to crystallize in urine.     

Pharmacokinetics of dibenzylamine administered in a sustained drug delivery system with cefazolin

The pharmacokinetics of dibenzylamine administered in a sustained drug delivery system with cefazolin was studied after i.m. administration of a dose of 1250 mg to healthy volunteers. The serum and urine levels of dibenzylamine were determined by a GLC technique using a specific nitrogen-phosphorus detector. Characterization of the kinetic parameters was performed by applying compartmental and non-compartmental analysis. Dibenzylamine was found to reach concentrations close to 300 ng ml-1 approximately 5 h after administration. The elimination constant had a value of 0.832 +/- 0.821 h-1 (mean +/- S.D.), which is higher than the release constant of the derivative (0.109 +/- 0.072 h-1) (mean +/- S.D.). These results show that release of dibenzylamine may be considered the limiting kinetic process, which governs the elimination of the product from the organism. Only a small amount of dibenzylamine is excreted in urine unchanged 3.43 +/- 3.28 per cent (mean +/- S.D.). Using the pharmacokinetic parameters calculated for dibenzylamine, a prediction has been made of the concentrations reached in a multiple dosage regimen after administration of a dose of 1250 mg every 24 h. The accumulation factor was 1.09.     

Altered gentamicin pharmacokinetics during the perioperative period

The effect of surgery on the pharmacokinetics of gentamicin sulfate in hospitalized patients was studied. Patients with cancer undergoing surgery of the head and neck were given gentamicin sulfate in doses calculated to achieve peak serum concentrations of 6-8 micrograms/mL and trough concentrations of 1-2 micrograms/mL. Each patient received a loading dose at the time of surgical incision, followed by five maintenance doses at eight-hour intervals. Steady-state peak and trough serum gentamicin concentrations were predicted using a one-compartment open pharmacokinetic model and literature values for volume of distribution (V) and first-order elimination rate constant (k). Serum gentamicin concentrations were measured 0.25 hours before and at 0.5, 3.5, and 6.5 hours after completion of infusion of the second maintenance dose. Peak and trough serum concentrations were obtained by extrapolation from these measured concentrations using weighted, nonlinear least squares regression. Predicted versus measured serum gentamicin concentrations and estimated versus observed values for V and k were compared. Eight men and seven women had evaluable serum gentamicin concentrations. Patients received a mean calculated maintenance dose of 4.4 +/- 0.7 mg/kg/day. Mean extrapolated peak and trough serum gentamicin concentrations were significantly lower than predicted, and observed values of V and k were significantly greater than estimated values. Gentamicin dosages calculated using standard pharmacokinetic variable values may not produce therapeutic concentrations in patients undergoing surgery. Monitoring of serum concentrations with dosage adjustment when indicated is necessary for optimal therapy in these patients.     

Prediction of serum vancomycin concentrations following intraperitoneal loading doses in continuous ambulatory peritoneal dialysis patients with peritonitis.

The pharmacokinetics of vancomycin were studied in continuous ambulatory peritoneal dialysis patients with peritonitis. Six patients received an intraperitoneal loading dose of 15 mg/kg and 4 received an intraperitoneal dose of 25 mg/L. The ability of 2 methods to predict serum concentrations during the loading dose exchange was determined. The mean serum concentration after the exchange was 17.8 +/- 2.2 mg/L in patients receiving the loading dose. The mean dialysis clearance in all patients was 0.94 +/- 0.34 L/h. 66.6 +/- 13.4% of a dose was absorbed into the circulation in 4 h. The volume of distribution was 0.61 +/- 0.46 L/kg, and the half-life for equilibration of vancomycin into the circulation from dialysate was 2.76 +/- 0.94 h. Two methods of predicting serum vancomycin concentrations were tested, with 1 method predicting values significantly different from measured concentrations while the other did not. Serum vancomycin concentrations can be accurately predicted during a loading dose exchange.     

Tazarotene does not affect the pharmacokinetics and efficacy of a norethindrone/ethinylestradiol oral contraceptive

OBJECTIVE: To determine the pharmacokinetic and pharmacodynamic interaction between oral tazarotene and an oral contraceptive containing norethindrone 1mg and ethinylestradiol 0.035 mg (Ortho-Novum 1/35).DESIGN: Two separate open-label, parallel-group, single-centre, pharmacokinetic and pharmacodynamic interaction studies.PARTICIPANTS AND METHODS: Twenty-seven healthy women (age 20-55 years) completed Study I, with a duration of 64 days during three consecutive menstrual cycles. Ortho-Novum 1/35 was taken once daily from study day 0 (first cycle day 1) to day 61 (third cycle day 6), and oral tazarotene 1.1 mg was coadministered daily from study day 34 (second cycle day 7) to day 61. Twenty-nine healthy women (age 20-44 years) completed Study II, with a duration of 75 days during three consecutive menstrual cycles. Ortho-Novum 1/35 was taken once daily from study day 0 (first cycle day 1) to day 74 (third cycle day 19), and oral tazarotene 6 mg was coadministered daily from study day 48 (second cycle day 21) to day 74. In both studies, the pharmacokinetics of tazarotenic acid on study day 61 (third cycle day 6) were evaluated from plasma tazarotenic acid concentrations. Pharmacokinetic parameters of plasma norethindrone and ethinylestradiol were compared before and after tazarotene administration (cycle day 6 of the second and third cycles, respectively). Serum luteinising hormone (LH) and follicle-stimulating hormone (FSH) concentrations were compared before and after tazarotene administration (cycle days 2, 4 and 6 of the second and third cycles, respectively). In Study II, serum progesterone concentrations were also determined on cycle days 18 and 20 of the second and third cycles. Tazarotenic acid was determined by liquid chromatography-tandem mass spectrometry. Ethinylestradiol and norethindrone were determined by gas chromatography-mass spectrometry. LH and FSH were assayed by microparticle enzyme immunoassay in Study I and by double-antibody radioimmunoassay in Study II. Progesterone was determined by solid-phase radioimmunoassay.RESULTS: In Study I (tazarotene 1.1 mg), the area under the plasma concentration-time curve from zero to 24 hours (AUC24) and the peak concentration in plasma (Cmax) for tazarotenic acid were 121 +/- 27 microg. h/L and 28.9 +/- 9.4 microg/L (mean +/- SD), respectively. In Study II (tazarotene 6 mg), AUC24 and Cmax for tazarotenic acid were 379 +/- 78 microg. h/L and 111 +/- 37 microg/L (mean +/- SD), respectively. In both studies, for both norethindrone and ethinylestradiol, the 90% CIs of AUC24 and Cmax on cycle day 6 before and after tazarotene administration were within the 80-125% boundary. In Study I, the 90% CIs of serum FSH and LH concentrations on cycle day 4 were within the 80-125% boundary. FSH and LH concentrations on cycle day 6 were marginally/partially outside the 80-125% boundary as a result of high variability. However, the mean FSH and LH serum concentrations on cycle day 6 of the third cycle were lower than those of the second cycle. In Study II, the 90% CIs of serum FSH, LH and progesterone concentrations were all within the 80-125% boundary, except for LH on cycle day 2. LH concentrations on cycle day 2 were marginally/partially outside the 80-125% boundary as a result of high variability. However, the mean serum LH concentration on cycle day 2 of the third cycle was lower than that of the second cycle.CONCLUSIONS: Oral tazarotene up to 6 mg once daily does not affect the pharmacokinetics and efficacy of Ortho-Novum 1/35.     

Toxicokinetics of phthalic acid: the common final metabolite of phthalic acid esters in rats

The toxicokinetic profiles of phthalic acid (PA), which is the common final metabolite of phthalic acid esters (PAE), were studied in rats after orally administering doses 20, 100, or 500 mg/kg. Concentrations of PA were determined in serum or urine by high-performance liquid chromatography (HPLC). The plasma concentrations of PA showed a biexponential increase following oral administration of doses ranging from 20 to 500 mg/kg. The terminal elimination half-lives (t1/2) of PA at dosages of 20, 100, or 500 mg/kg were 6.46 +/- 1.13, 5.19 +/- 3.56, and 5.10 +/- 1.10 h, respectively, total clearances (Cl/F) of PA at 20, 100, or 500 mg/kg were 97.43 +/- 4.20, 215.01 +/- 55.42, and 721.07 +/- 51.81 ml/h, and apparent distribution volumes of PA in the steady state (Vz/F) at 20, 100, or 500 mg/kg were 903.28 +/- 125.28, 1419.87 +/- 527.53, and 5264.86 +/- 993.65 ml, respectively. PA was absorbed rapidly after an oral dose of 500 mg/kg with peak concentration (Cmax) in blood (3.5 +/- 0.33 microg/ml) at 30 min postadministration. After oral administration, the dose-normalized area under the curve (AUC) (146.90 +/- 9.33 microg/h/ml) for 500 mg/kg was significantly greater than at 20 mg/kg (44.69 +/- 2.56 microg/h/ml). Urine analysis indicated that 13 +/- 0.45% of the administered PA dose (at 500 mg/kg, p.o.) was recovered unchanged in urine within 24 h. Data concerning the toxicokinetic profiles of PA improve our understanding of the toxicological potential of PAE and may prove useful for risk assessments of multiple phthalates exposure.