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PubMed1998

Impaired glucose tolerance: what are the clinical implications?

Impaired glucose tolerance (IGT) was standardized in 1979 by the National Diabetes Data Group and the World Health Organization as a risk factor for type 2 diabetes, replacing groups such as 'borderline' and 'chemical' diabetes. IGT was defined by a blood/plasma glucose value 2 h after a 75 g glucose load that was clearly abnormal but did not convey a risk of microangiopathy in those with non-diabetic fasting blood/plasma glucose levels. IGT is not uncommon, having a prevalence of 2-25% in adults. Determinants include age, obesity (total and central), family history of type 2 diabetes, physical inactivity and triglyceride levels. The main clinical significance of IGT is: (1) as a risk factor for type 2 diabetes, with 20-50% of individuals developing type 2 diabetes over 10 years; (2) as a risk factor for cardiovascular disease (CVD); and (3) as a component of the metabolic syndrome. IGT can be treated and this may prevent or delay progression to type 2 diabetes, though the effect of treatment on the risk of CVD is unknown.

Cardiovascular Diseases↗

PubMed2001

Pharmacokinetics of bupivacaine after continuous epidural infusion in infants with and without biliary atresia.

BACKGROUND: Continuous epidural infusion of bupivacaine is widely practiced for postoperative pain relief in pediatric patients. However, bupivacaine may induce adverse effects in infants (convulsions or cardiac arrhythmias), likely because of decreased hepatic clearance and serum protein binding capacity. The authors wanted to examine the complex relations between age, alpha-1 acid glycoprotein (AAG) concentration, and unbound and total bupivacaine serum concentrations in infants receiving bupivacaine epidurally for 2 days. METHODS: Twenty-two infants aged 1-7 months (12 with biliary atresia and 10 with another disease) received a continuous epidural infusion of 0.375 mg x kg(-1) x h(-1) bupivacaine during 2 days (during and after surgery). Unbound and total bupivacaine concentration in serum was measured 0.5, 4, 24, and 48 h after infusion initiation. AAG concentration was measured in serum before and 2 days after surgery. In eight additional infants, the blood/plasma concentration ratio was measured in vitro at whole blood concentrations of 2 and 20 microg/ml. Bupivacaine concentration was fitted to a one-compartment model to calculate basic pharmacokinetic parameters. RESULTS: No adverse effects were observed. AAG increased markedly after surgery, and the increase was correlated to both age and preoperative AAG concentration. Two infants aged 1.8 months had unbound concentrations greater than 0.2 microg/ml. Clearance of unbound drug significantly increased with age. Because of increased drug binding, clearance of bound drug decreased both with time (from 0.5 to 48 h) and with age. Blood/plasma ratio was 0.77+/-0.08 and 0.85+/-0.24 at 2 and 20 microg/ml, respectively. CONCLUSIONS: Because of a low AAG concentration and a low intrinsic clearance, unbound bupivacaine increased to concentrations greater than 0.2 microg/ml in two infants younger than 2 months, after 2 days of infusion at a rate of 0.375 mg x kg(-1) x h(-1). The increase in AAG observed after surgery did not fully buffer this unbound fraction. Similarly, the buffer capacity of erythrocytes did not sufficiently increase at high concentration to compensate the saturation of the AAG system. Thus, we propose the use of a maximum dose of 0.25 mg x kg(-1) x h(-1) in infants younger than 4 months and a maximum of 0.3 mg x kg(-1) x h(-1) in infants older than 4 months.

Aging↗

PubMed1978

Pharmacokinetics of clomethiazole in healthy adults.

The systemic availability of clomethiazole was assessed by comparing blood levels after intravenous and oral administration. Clomethiazole was rapidly absorbed after oral administration to volunteers, particularly when administered as syrup. The fraction of the given dose that reached the systemic circulation after 1 capsule of clomethiazole (192 mg clomethiazole) was 0.25 +/- 0.18, after 2 capsules (384 mg clomethiazole) 0.38 +/- 0.18, and after 15 ml syrup (480 mg clomethiazole) 0.42 +/- 0.20. The time-blood concentration profiles were consistent with a two-compartment open model and the mean elimination half-lives of 3.6--5.0 hrs. were found for the different formulations and administration routes. Elimination half-lives showed little variation and a mean systemic clearance of 49 ml/min./kg was found for clomethiazole after intravenous administration. Clomethiazole is bound to human plasma proteins (63.4 +/- 1.6%, 37 degrees), a binding which is not affected by Vacutainer sample tubes. The blood/plasma distribution of clomethiazole was 0.76 +/- 0.02 at 37 degrees. A sensitive mass fragmentographic assay for the determination of clomethiazole in blood/plasma down to levels of 1 ng/ml (6.2 nmol/l) is described.

Administration, Oral↗

PubMed1987

Amiodarone and desethylamiodarone tissue uptake in rats chronically treated with amiodarone is non-linear with the dose.

Four groups of rats were given amiodarone chronically at 25, 37.5, 50, 75 mg kg-1/12 h for 3 weeks; on day 21 the animals were killed and blood, plasma, heart, lung, liver and fat were collected and assayed for amiodarone and desethylamiodarone. Amiodarone plasma concentrations ranged from 0.74 to 4.68 micrograms mL-1 and desethylamiodarone from 0.08 to 2.05 micrograms mL-1. Plasma, blood and tissue concentrations of amiodarone and desethylamiodarone increased significantly with the dose. Blood/plasma and tissue/plasma partition ratios of amiodarone and desethylamiodarone increased significantly at the higher doses. Blood/plasma ratio was a good predictor of tissue/plasma ratios of amiodarone and its metabolite, except in fat. Total phospholipid concentrations in lung were correlated with amiodarone and desethylamiodarone concentrations in plasma, blood and lung.

Amiodarone↗

PubMed1989

Pharmacokinetics and bioavailability of carbovir, a carbocyclic nucleoside active against human immunodeficiency virus, in rats.

Carbovir is a novel carbocyclic nucleoside which has been shown to have potent in vitro activity against human immunodeficiency virus, the causative agent of acquired immunodeficiency syndrome. Sprague-Dawley male rats were used to investigate the pharmacokinetics and bioavailability of carbovir. Six rats received carbovir (20 mg/kg of body weight) through the jugular vein, and blood samples were collected through the femoral vein 2, 5, 10, 15, 20, 30, 45, 60, 75, 90, 120, 150, 180, and 240 min after the dose. Four of these rats also received a 60-mg/kg oral dose of carbovir, and a similar blood sampling schedule was followed. Whole-blood samples were prepared by solid-phase extraction, and the carbovir concentration in the samples was analyzed by reversed-phase high-pressure liquid chromatography. The profile of carbovir concentration in blood versus time after the intravenous dose was biexponential, with a very rapid distribution phase. Terminal elimination half-life was 21.4 +/- 4.37 min, and total body clearance was 55.2 +/- 13.8 ml/min per kg, which was within the range of the hepatic blood flow. The volume of distribution at steady state was 1,123 +/- 250 ml/kg. The blood/plasma ratio and the plasma protein binding of carbovir in rat blood were determined in vitro by ultrafiltration. The plasma protein binding of carbovir was only 20% and was not concentration dependent. However, the blood/plasma ratio decreased significantly as concentration increased, indicating saturable binding sites in erythrocytes. After the oral dose, the terminal half-life was 81.0 +/- 67.6 min, indicating that oral carbovir followed "flip-flop" kinetics, with absorption being much slower than elimination of the drug from the body. Oral bioavailability was 0.101 +/- 0.035. Double peaks were present in the concentration-time profile for each rat receiving the oral dose, indicating either a delay in stomach emptying of the drug or slow dissolution of precipitated carbovir in the stomach and upper small intestine.

Animals↗

PubMedDate not supplied

Use of autologous blood in general surgery.

BACKGROUND/AIMS: Autologous blood predonation is still not as widespread as it should be in general surgery practice, even if the method is well-known and has benefits established in international literature. Authors describe the impact of an autotransfusion program, in a general surgery university department, focusing on management and cost problems. METHODOLOGY: A description of the efficacy of the program during a yearlong activity period is presented. An analysis has been made about the quantity of predonated blood/plasma units, the quantity actually transfused and use of homologous blood. The problems which occurred and the cost are discussed. RESULTS: The most used autotransfusion method was preoperative predeposit of autologous blood. The analysis of results focused on some organizational problems that need to be avoided in order to show the methods maximum benefits. In a large number of cases (some 50%) predeposit was not made because of several managing/technical problems. In another large number of cases (38%) the quantity of units predonated did not fully supply the needs and several patients received homologous products. In another number of cases predonated blood units were not used at all (61/34%). CONCLUSIONS: Predeposit, preoperative hemodilution and intraoperative recovery, are methods that should all be available in a general surgery department to manage in the best way the single patients blood/plasma needs, reducing post-transfusion complication. To optimize the program and minimize waste some guidelines must be established, with the aim of a rational and correct use of the procedure. Despite the value of the method, and the favor encountered by the patients, we must not forget that the use of autologous blood is not costless.

Blood Transfusion, Autologous↗

PubMed2006

Epidemiology, clinical and laboratory characteristics of currently alive HIV-1 infected former blood donors naive to antiretroviral therapy in Anhui Province, China.

BACKGROUND: Unregulated commercial blood/plasma collection among farmers occurred between 1992 and 1995 in central China and caused the second major epidemic of human immunodeficiency virus type 1 (HIV-1) infection in China. It is important to characterize HIV-1-infected former blood donors and to study characteristics associated with disease progression for future clinical intervention and vaccine development. METHODS: A cross-sectional study was performed on HIV-1-infected former blood donors (FBDs) and age-matched HIV-seronegative local residents. Demographic, epidemiologic, clinical and key laboratory data were collected from all study participants. Both unadjusted and adjusted multivariate linear regressions were employed to analyze the association of the decrease of CD4(+) T-cell counts with other characteristics. RESULTS: Two hundred and ninety-four HIV-1-infected FBDs and 59 age-matched HIV-seronegative local residents were enrolled in this study. The unregulated blood/plasma collection occurred more than a decade (10.8 - 12.8 years) ago, which caused the rapid spread of HIV-1 infection and the high prevalence of co-infection with hepatitis C virus (HCV, 89.5%); hepatitis B virus (HBV) co-infection was observed in only 11 HIV(+)participants (3.7%). Deterioration in both clinical manifestation and laboratory parameters and increase of viral loads were observed in parallel with the decrease of CD4(+) T-cell counts. The decrease of total lymphocyte counts (P < 0.001) and hemoglobin levels (P < 0.001) and the appearance of dermatosis (P = 0.03) were observed in parallel with the decrease of CD4(+) T-cell counts whereas viral loads (P < 0.001) and CD8(+) T-cell counts (P = 0.01) were inversely associated with CD4(+) T-cell counts. CONCLUSIONS: Co-infection with HCV but not HBV is highly prevalent among HIV-1-infected FBDs. CD4(+) T-cell counts is a reliable indicator for disease progression among FBDs. Total lymphocyte counts, hemoglobin level and appearance of dermatosis were positively associated with CD8(+) T-cell counts and viral loads were inversely associated with the decreased CD4(+) T-cell counts.

Adult↗

PubMed1983

Effects of competitive red blood cell binding and reduced hematocrit on the blood and plasma levels of [14C]Indapamide in the rat.

The effects of chlorthalidone and acetazolamide on the red blood cell binding of indapamide were investigated. Both drugs caused a substantial decrease in the amount of indapamide bound to the erythrocytes in vitro. This effect was demonstrated by a change in the indapamide blood/plasma ratio from approximately 6 in control samples, to a value of 1 when either of the displacing agents was added. Coadministration of acetazolamide with 14C-labeled indapamide to rats, resulted in a 5-fold drop in the blood levels of total radioactivity, relative to rats dosed with [14C]indapamide alone. Concomitantly, there was a 2-fold increase in the plasma levels of total radioactivity after acetazolamide coadministration. In rats whose hematocrits had been reduced by extensive bleeding, there were only minor alterations in the blood/plasma partitioning of [14C]indapamide. Thus, chlorthalidone and acetazolamide were able to displace indapamide from erythrocytes in vitro and in vivo, possibly by competition at a carbonic anhydrase binding site. The pharmacokinetics of drugs which are extensively bound to erythrocytes may be significantly altered by the presence of other agents capable of competitive binding.

Acetazolamide↗

PubMed1993

Monitoring of cyclosporin A levels with radioimmunoassay in renal transplant recipients: comparison of monospecific and nonspecific assays.

Patients receiving cyclosporin A (CsA) therapy should be monitored carefully in order to avoid side effects and maintain immunosuppression. Radioimmunoassay is one of the most commonly used methods of monitoring CsA levels. The decision to use whole blood vs plasma or monospecific vs nonspecific monoclonal antibodies for the measurement of CsA levels has been a controversial issue. In this study, CsA levels in the whole blood and plasma were measured simultaneously with INCSTAR specific monoclonal antibodies in 20 renal transplant recipients (group A). There was a significant correlation between the CsA levels in the whole blood and plasma (R2 = 0.7379, p < 0.00001). However, at the therapeutic limit, the correlation was not good. The whole blood/plasma CsA concentration ratios were not correlated with the hematocrits of the patients. In another group of 20 renal transplant recipients (group B), CsA levels in whole blood and plasma were measured simultaneously with INCSTAR nonspecific monoclonal antibodies. There was a significant correlation between the CsA levels in whole blood and plasma (R2 = 0.6714, p < 0.00001). The whole blood/plasma ratios were significantly correlated with the hematocrits (R2 = 0.5457, p = 0.0002). The later finding could be due to the extensive cross-reactivity of nonspecific monoclonal antibodies with CsA metabolites, which are almost exclusively bound to the erythrocytes. The hematocrits in renal transplant recipients usually show significant change over a period of time. The plasma level may be more stable in such cases. However, measurement of whole blood levels also has several advantages, mainly from a technical aspect.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclosporine↗

PubMed2003

Impact of Solutol HS 15 on the pharmacokinetic behaviour of colchicine upon intravenous administration to male Wistar rats.

In the current investigation, the alkaloid colchicine was administered intravenously to male Wistar rats both as a solution in isotonic sodium chloride (NaCl 0.9%, control group) and in NaCl 0.9%:Solutol HS 15 (95:5) at 1.5 mg/kg. At predetermined time points, plasma and urine were collected from the animals and analysed for colchicine and its demethylated metabolites by LC/MS-MS. In the presence of Solutol HS 15, colchicine clearance (CI) was significantly decreased and its maximum plasma concentration (c(max)) was significantly increased as compared to the control group (CI: 15.6+/-7.0 ml/min/kg vs 34.3+/-2.3 ml/min/kg; c(max) 3055.1+/-587.4 h vs 1260.1+/-223.7 h; p<0.05). Moreover, the amount of parent colchicine excreted into urine was markedly increased in the Solutol HS 15 treated group (41.50+/-3.23 vs 1.17+/-0.41% of total dose; p<0.05). By contrast, there was no statistically significant difference but a trend to lower values only in the volume of distribution (V(d) 13.3+/-2.2 l/h vs 31.4+/-17.7 l/h, p=0.35). The half-lives for the first (t(1/2 1stphase). 0.21+/-0.02 h vs 0.20+/-0.03 h) and second phase (t(1/2 2ndphase). 18.5+/-6.9 h vs 18.3+/-7.7 h) did not differ significantly in dependence on the dosing vehicle. The free fraction in rat plasma (FF), the blood/plasma (lambda) and erythrocyte/plasma concentration ratios (K(e)) were not significantly changed in the presence of different concentrations of Solutol HS 15 compared with surfactant-free incubations (overall means: 72.25+/-0.50% for FF, 0.80+/-0.02 for lambda, 0.46+/-0.04 for K(e)). In vitro, in rat hepatocytes, the clearance of colchicine was significantly reduced at 0.003% Solutol HS 15 present in the incubation medium (0.86+/-0.15 microl/min/10(-6) cells vs 1.46+/-0.06 microl/min/10(-6) cells). As colchicine exhibits a comparatively high aqueous solubility, an impact of Solutol HS 15 on the solubility of the alkaloid is very unlikely to be a reason for the observed effect. Therefore, our results indicate that the most likely reasons for the changed pharmacokinetic behaviour of colchicine in the presence of Solutol HS 15 are alterations of metabolism and/or transport as well as distribution and elimination processes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1978

Disposition of meperidine in pregnancy.

Plasma concentration-time profiles of meperidine after intravenous administration to 7 pregnant women during labor were investigated. There was considerable interpatient variation in initial plasma concentrations of meperidine and its volume of distribution. When the data in the literature on the disposition of meperidine in nonpregnant subjects were used for comparison, it was found that the initial dilution volume (V1), the volume of distribution at steady-state (Vss), and the apparent volume of distribution during the terminal exponential phase of drug elimination (Vbeta) were less (p less than 0.05) in pregnant subjects than in healthy nonpregnant control subjects but were not significantly different in pregnant subjects and nonpregnant surgical patients. Mean total systemic blood clearance was also significantly less in the pregnant subjects (843 ml/min) than previously reported for healthy nonpregnant control subjects (1,465 ml/min). The blood/plasma concentration ratio of meperidine in pregnant women (0.940) was higher than that in control subjects (0.768; p less than 0.01). Placental transfer of meperidine was investigated in 4 of the patients; in 2 the concentration of the drug was greater in cord plasma than in maternal plasma. Further study is indicated.

Adolescent↗

PubMed1993

Acadesine (AICA-riboside): disposition and metabolism of an adenosine-regulating agent.

Acadesine (AICA-riboside) is a purine nucleoside analog with anti-ischemic properties that is currently being studied (Phase 3) for the prevention of adverse cardiovascular outcomes in patients undergoing coronary artery bypass graft (CABG) surgery. The safety, tolerance, and pharmacokinetics of the drug have previously been reported in this journal (J Clin Pharmacol 1991; 31:342-347). Recently, the authors studied the disposition and metabolism of acadesine in healthy males (n = 4) after a 15-minute intravenous infusion of 25 mg/kg of 2-14C-acadesine. The postinfusion total 14C concentrations in plasma declined in a multiexponential manner, and the terminal phase had an apparent t1/2 of about 1 week. Intact acadesine was only measurable for 2 hours after infusion. Total plasma clearance was 2.2 +/- 0.2 L/hour/kg, the acadesine blood/plasma ratio was unity, and plasma protein binding was negligible (approximately 1%). Uric acid, the end product of purine metabolism in humans, was the major metabolite of acadesine in plasma and accounted for all of the total, plasma 14C at 6 hours after infusion. In whole blood, acadesine 5'-monophosphate was present in the red blood cells, and the nucleotide represented 30% of the total blood 14C at the end of the infusion. The nucleotide was confined to the RBCs and was not present in plasma. Urine and fecal recoveries over 2 weeks accounted for 48% of the total 14C dose, with 44% excreted in urine and 4% in feces. Only 5% of the dose was excreted in urine as intact acadesine. Uric acid was the major metabolite in urine together with small amounts of hypoxanthine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMedDate not supplied

Toxicokinetics of bromodichloroacetate in B6C3F1 mice.

The oral and i.v. elimination kinetics were investigated for bromodichloroacetate (BDCA), a haloacetate found in drinking water. The BDCA was administered at a dose of 5, 20 and 100 mg kg-1 to B6C3F1 mice and appears to distribute to the total body water with a mean volume of distribution of 427 +/- 79 ml kg-1. It is subject to first-pass hepatic metabolism with a range of bioavailabilities of 0.28-0.73. A mean terminal half-life of 1.37 +/- 0.21 h. was calculated from the two lower doses of both i.v. and oral administration. Non-linear behavior was exhibited at doses greater than 20 mg kg-1, with a much higher than expected area under the curve (AUC), a decrease in total body clearance (CL(b)) and an increase in the terminal half-life to 2.3 h at the highest dose. The average CL(b) was 220 ml h(-1) kg-1 for the lower two doses but decreased to 156 ml h(-1) kg-1 at the high dose. The BDCA is primarily eliminated by metabolism, with only 2.4% of the parent dose being recovered in the urine at the high dose. The unbound renal clearance, as calculated from the high dose, was 15.0 ml h(-1) kg-1. The BDCA is moderately bound to plasma proteins (f(u) = 0.28) and preferentially distributes to the plasma with a blood/plasma ratio of 0.88.

Acetates↗

PubMed2004

Effect of mild and moderate hepatic impairment on azimilide pharmacokinetics following single dose oral administration.

Azimilide dihydrochloride (75-125 mg/day) is currently being developed for use in prolonging the time to recurrence of atrial fibrillation/flutter and for reducing the frequency of shocks in patients with an implantable cardioverting defibrillator. This study investigated the influence of mild and moderate hepatic impairment on azimilide pharmacokinetics. Six subjects each with mild and moderate hepatic impairment (Child-Pugh grades A and B, respectively) were age, weight, smoking status, and gender-matched to a healthy subject (total N = 24). Each subject was administered a single, oral dose of 100 mg azimilide dihydrochloride following an overnight fast. Blood/plasma and urine samples were collected up to 28 days and over 9 days, respectively, and analyzed using HPLC with MS/MS or UV detection. For azimilide, most parameters in subjects with mild to moderate hepatic impairment were within 25% of those observed in matched healthy subjects, with no statistically significant differences observed. For F-1292 (major metabolite in plasma), a significant decrease in AUC was observed in subjects with moderate hepatic impairment, secondary to an increase in renal clearance (CL(r)). Based on these results, no a priori dosage adjustment is required in subjects with mild to moderate hepatic impairment.

Administration, Oral↗

PubMed2000

Quantitative whole-body radioluminography-future strategy for balance and tissue distribution studies.

The present routine to conduct balance and/or tissue dissection distribution studies has now and then been questioned, because the way they are generally conducted does not produce information in proportion to the spending of animal and personnel resources. Usually only total radioactivity is measured and due considerations are not always taken to the metabolic fate of the label. In this study a different strategy is presented-integrating quantitative whole-body radioluminography and different chromatographic methods on extracts of tissue pieces punched from the whole-body sections. In addition to the saving in cost and time, the proposed integrated whole-body radioluminographic/metabolic profile protocol will provide (i) a detailed picture of the distribution of radioactivity at selected dose levels and time points in male, female, and pregnant animals; (ii) the time course of radioactivity in blood/plasma and tissues selected from the images (approximate half-life and AUC); (iii) accumulated urinary and fecal excretion of radioactivity and an estimate of the proportion of radioactive metabolites; (iv) tissue information about the proportion of parent drug versus metabolites of pieces punched from the whole-body sections; and (v) indications of possible tissue binding.

Animals↗

PubMed1997

A physiologically based pharmacokinetic and pharmacodynamic model for paraoxon in rainbow trout.

Trout were exposed to an aqueous solution of 75 ng/ml paraoxon for 5 days at 12 degrees C. The relationships among paraoxon concentration in water and target organs, AChE inhibition, and carboxylesterase (CaE) detoxification of paraoxon were characterized quantitatively by development of a PBPK-PD model. The PKPD model structure consisted of brain, heart, liver, kidney, and remainder of the body, which were interconnected by blood circulation. The paraoxon tissue/blood partition coefficients were: plasma/water, 1.46; liver/plasma, 5.89; brain/plasma, 3.90; heart/plasma, 2.91; kidney/plasma, 0.45; and blood/plasma, 0.91. Turnover of AChE was characterized from a dose-response study, in which its zero-order synthesis rate and first-order degradation rate constant were determined in several tissues; for brain they were 7.67 pmol/min and 7.31 x 10(-5) hr(-1). The uptake and depuration clearances of paraoxon (Cl(u) = 0.651 and Cl(d) = 0.468 ml min(-1) g body wt(-1)) were determined using a compartmental model. During continuous water exposure to paraoxon, AChE activity in the tissues declined to new steady state values that were maintained by the synthesis of new AChE. CaE was shown by simulation to be an important pathway for detoxification of paraoxon.

Acetylcholinesterase↗

PubMed1982

A pharmacokinetic study of mianserin.

The kinetics of mianserin have been evaluated in eight healthy male volunteers following a single oral dose of 60 mg. Plasma and blood concentrations of mianserin were measured by gas chromatography-mass fragmentography. The peak blood concentration observed was 65 microgram/1 at 3 h following the dose. Mean kinetic parameters (and range) calculated from the blood concentrations were: (t1/2)abs 1.1 h (0.3-2.8), (t1/2) alpha 2.5 h (0.9-4.7), (t1/2) beta 21 h (14-33), (Vd) beta 27.5 l/kg (16.8-46.5) and Cloral 0.98 l/kg/h (0.47-1.75). Blood/plasma concentration ratios ranged from 0.50-0.74.

Administration, Oral↗

PubMed1987

Nonlinear pharmacokinetic characteristics of 5-fluorouracil (5-FU) in colorectal cancer patients.

The nonlinear disposition kinetics of 5-fluorouracil (5-FU) were investigated in 6 patients with colorectal carcinoma. Each patient randomly received two single, intravenous doses of 5-FU (7.5 and 15 mg/kg) on separate days. Venous blood and urine samples were collected just prior to and for 5 h after drug administration. In addition to the kinetic studies, the in vitro whole blood/plasma concentration ratio and stability of 5-FU at 37 degrees C were determined in whole blood from normal volunteers and from 5 patients with colorectal carcinoma. A disproportionate increase in area under the curve and corresponding decrease in total body clearance with increasing dose was observed suggesting dose-dependent behavior of 5-FU. Doubling the dose was accompanied by a 36% decrease in nonrenal clearance but no apparent change in renal clearance. Therefore, the mechanism for dose-dependent elimination appears to be primarily associated with nonrenal processes. The mean 5-FU half-life following the high dose was nearly twice as long as that observed for the low dose (12.3 versus 6.2 min). The log-linear decline in plasma concentrations and increase in half-life with dose suggest the potential role of product-inhibition as an explanation for the observed nonlinearity in 5-FU elimination. The present study demonstrates that 5-FU degrades when incubated in whole blood. This most likely reflects metabolism in red blood cells or other blood-formed elements since 5-FU was stable in plasma. Although degradation in whole blood occurs, the estimated whole blood clearance does not contribute significantly to the observed total body clearance value. The findings suggest the possibility of pulmonary clearance of 5-FU.

Adult↗