Fractionated administration of high-dose cyclophosphamide: influence on dose-dependent changes in pharmacokinetics and metabolism

PURPOSE: The alkylating agent cyclophosphamide (CP) is a prodrug that is metabolized to both cytotoxic and inactive compounds. We have previously shown that following dose escalation from conventional-dose (CD) to high-dose (HD) levels; the fraction of the dose cleared by bioactivation is significantly decreased (66% versus 48.5%) in favor of inactivating elimination pathways when the HD is given as a single 1-h infusion. Based on the concept of bioactivating enzyme saturation with increasing doses, we investigated the influence of fractionated application of HD-CP on dose-dependent changes in metabolism. PATIENTS AND METHODS: Plasma concentrations of CP (measured by high-performance liquid chromatography, HPLC) and urinary concentrations of CP and its major metabolites (quantified by [31P]-nuclear magnetic resonance spectroscopy; [31P]-NMR spectroscopy), were determined in four patients with high-risk primary breast cancer who received adjuvant chemotherapy including both CD-CP (500 mg/ m2 infused over 1 h) and split HD-CP (50 mg/kg infused over 1 h on each of 2 consecutive days (d): d1 and d2. RESULTS: (Data are given as mean values for CD and d1/d2 of HD, respectively). Systemic clearance (CL) of CP was similar during CD and d1 of HD, but significantly increased on d2 of HD (CL: 83 and 78/115 ml/min; P < 0.01 for d1 versus d2). The latter was translated into an increase in formation CL of both active (+ 16.4 ml/min) and inactive metabolites (+ 17.6 ml/ min) and reflects autoinduction of metabolism. As compared with CD-CP, no statistically significant decrease was observed in the relative contribution of bioactivation CL to overall CL during both days of HD (63% versus 57%/53%). Recovery of intact CP in 24-h urine corresponded to 24%, 29%, 22% of the dose (P < 0.05 for d1 versus d2 of HD). CONCLUSIONS: Following dose escalation of CP, dividing the high dose over 2 days instead of one single infusion may favorably impact the metabolism of CP in terms of bioactivation. In addition, on day 2 of a split regimen, renal elimination of CP is decreased, which implies that more drug is available for metabolism.     

Pharmacokinetics of oral and intravenous dolasetron mesylate in patients with renal impairment

In an open-label, randomized, two-way complete crossover study, the influence of renal impairment on the pharmacokinetics of dolasetron and its primary active metabolite, hydrodolasetron, were evaluated. Patients with renal impairment were stratified into three groups of 12 based on their 24-hour creatinine clearance (Cl(cr)): group 1, mild impairment (Cl(cr) between 41 and 80 mL/min); group 2, moderate impairment (Cl(cr) between 11 and 40 mL/min); and group 3, endstage renal impairment (Cl(cr) < or = 10 mL/min). Twenty-four healthy volunteers from a previous study served as the control group. Each participant received a single intravenous or oral 200-mg dose of dolasetron mesylate on separate occasions. Serial blood samples were collected up to 60 hours after dose for determination of dolasetron and hydrodolasetron, and urine samples were collected in intervals up to 72 hours for determination of dolasetron, hydrodolasetron, and the 5' and 6'-hydroxy metabolites of hydrodolasetron. Because plasma concentrations were low and sporadic, pharmacokinetic parameters of dolasetron were not calculated after oral administration. Although some significant differences in area under the concentration-time curve (AUC0-infinity), volume of distribution (Vd), systemic clearance (Cl), and elimination half-life (t1/2) of the parent drug were observed between control subjects and patients with renal impairment, there were no systematic findings related to degree of renal dysfunction. The elimination pathways of hydrodolasetron include both hepatic metabolism and renal excretion. Consistent increases in mean Cmax, AUC0-infinity, and t1/2 and decreases in renal and total apparent clearance of hydrodolasetron were seen with diminishing renal function after intravenous administration of dolasetron mesylate. No consistent changes were found after oral administration. Urinary excretion of hydrodolasetron and its metabolites decreased with decreasing renal function, but the profile of metabolites remained constant. Dolasetron was well tolerated in all three groups of patients. Based on these findings, no dosage adjustment for dolasetron is recommended in patients with renal impairment.     

Dexamethasone pharmacokinetics in clinically normal dogs during low- and high-dose dexamethasone suppression testing

Dexamethasone pharmacokinetics was studied in 10 healthy dogs receiving high-dose administration of dexamethasone (dosage, 0.1 mg/kg of body weight, IV), alone or combined with ACTH (dosage, 0.5 U/kg, IV), or low-dose administration of dexamethasone (dosage, 0.01 mg/kg, IV) in an incomplete cross-over design. Serum samples were obtained at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 720, 1,080, 1,440, 1,920, 2,400, and 2,880 minutes after dexamethasone administration; dexamethasone was measured by radioimmunoassay validated for use in dogs. Dexamethasone pharmacokinetics was adequately described by a two-compartment first-order open model. Comparison of pharmacokinetics for the low- and high-dose protocols revealed dose dependence; area under the curve, mean residence time, clearance, and volume of distribution increased significantly when dexamethasone dosage increased. The elimination rate constant was significantly (P < 0.05) less, and the elimination half-life significantly greater for the high-dose protocols; however, the distribution rate constant and distribution half-life were not significantly different when high-dose protocols were compared with the low-dose protocol. Dose-dependent increases in volume of distribution and clearance may be related to saturation of protein-binding sites. Concurrent administration of ACTH did not affect dexamethasone disposition.     

Sublethal damage repair capacity in carcinoma cell lines with p53 mutations

The pharmacokinetics of furosemide were investigated in anaesthetized horses with bilateral ureteral ligation (BUL) with (n = 5) or without (n = 5) premedication with phenylbutazone. Horses were administered an intravenous (i.v.) bolus dose of furosemide (1 mg/kg) approximately 60-90 min after BUL. Plasma samples collected up to 3 h after drug administration were analysed by a validated high performance liquid chromatography method. Median plasma clearance (CLp) of furosemide in anaesthetized horses with BUL was 1.4 mL/min/kg. Apparent steady state volume of distribution (Vd(ss)) ranged from 169 to 880 mL/kg and the elimination half life (t1/2) ranged from 83 min to 209 h. No differences in plasma concentration or kinetic parameter estimates were observed when phenylbutazone was administered before furosemide administration. BUL markedly reduces the elimination of furosemide in horses and models the potential effects that severe changes in kidney function may have on drug kinetics in horses.     

Predicting etoposide toxicity: relationship to organ function and protein binding

PURPOSE: To investigate the effect of organ function on total and free etoposide pharmacokinetics and hematologic toxicity. PATIENTS AND METHODS: Seventy-two patients who received single-agent intravenous (i.v.) etoposide over 5 or 8 days (total dose, 500 mg/m2) were studied. Pharmacokinetic parameters were derived after analysis of total plasma etoposide by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection, and etoposide protein binding by ultrafiltration of an etoposide-spiked, pretreatment serum sample, followed by HPLC analysis. Free etoposide area under the concentration-time curve (AUC) was derived from the total AUC and protein binding. RESULTS: Patients with renal impairment (serum creatinine level > 130 mumol/L) had a lower plasma etoposide clearance (13.6 v 18.5 mL/min/m2; P = .016), resulting in an increased total-drug and free-drug AUC (total etoposide AUC 615 v 452 micrograms/mL.hr; P = .016; free etoposide AUC 26.0 v 17.6 micrograms/mL.hr; P = .026) and increased hematologic toxicity (nadir neutrophil count 0.3 v 1.9 x 10(9)/L; P = .005). Patients with albumin levels less than 35 g/L had no change in total etoposide kinetics but had an increase in unbound etoposide (5.2% v 4.1%; P = .01), resulting in an increase in free etoposide AUC (27.5 v 16.5 micrograms/mL.hr; P = .003) and more profound toxicity (nadir neutrophil count 0.6 v 1.9 x 10(9)/L; P = .004). In patients with normal albumin and creatinine, increased toxicity in those older than 65 years was associated with a reduced drug clearance, and in those with increased liver enzymes by a trend toward an increase in free etoposide AUC. CONCLUSION: Increased hematologic toxicity after etoposide in patients with abnormal organ function is mediated by an increase in free etoposide AUC. A reduction in dose is clearly indicated in such patients.     

Reversal of medetomidine-induced sedation in reindeer (Rangifer tarandus tarandus) with atipamezole increases the medetomidine concentration in plasma

The pharmacokinetics of two potent alpha 2-adrenoceptor agents that can be used for immobilization (medetomidine) and reversal (atipamezole) of the sedation in mammals, were studied in three reindeer (Rangifer tarandus tarandus) in winter and again in summer. Medetomidine (60 micrograms/kg) was injected intravenously (i.v.), followed by atipamezole (300 micrograms/kg) intravenously 60 min later. Drug concentrations in plasma were measured by HPLC. The administration of atipamezole resulted in an immediate 2.5-3.5 fold increase in the medetomidine concentration in plasma. Clearance for medetomidine (median 19.3 mL/min.kg) was lower than clearance for atipamezole (median 31.0 mL/min.kg). The median elimination half-lives of medetomidine and atipamezole in plasma were 76.1 and 59.9 min, respectively. The animals became resedated 0.5-1 h after the reversal with atipamezole. Resedation may be explained by the longer elimination half-life of medetomidine compared to atipamezole.     

Renal dysfunction does not alter the pharmacokinetics or LDL-cholesterol reduction of atorvastatin

The objective of this study was to determine the effects of renal dysfunction on the steady-state pharmacokinetics and pharmacodynamics of atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Nineteen subjects with calculated creatinine clearances ranging from 13 mL/min to 143 mL/min were administered 10 mg atorvastatin daily for 2 weeks. Pharmacokinetic parameters and lipid responses were analyzed by regression on calculated creatinine clearance. Correlations between steady-state atorvastatin pharmacokinetic or pharmacodynamic parameters and creatinine clearance were weak and, in general, did not achieve statistical significance. Although the elimination rate constant, lambda z (0.579), was significantly correlated with creatinine clearance, neither maximum plasma concentration (Cmax, -0.361) nor oral clearance (Cl/F, 0.306) were; thus, steady-state exposure is not altered. Renal impairment has no significant effect on pharmacodynamics and pharmacokinetics of atorvastatin.     

Clinical pharmacokinetics of escalating i.v. doses of dexanabinol (HU-211), a neuroprotectant agent, in normal volunteers

The pharmacokinetics of dexanabinol (HU-211), a synthetic, nonpsychotropic cannabinoid with neuroprotectant action, was evaluated in a phase I clinical trial. The compound was administered at doses of 48 mg, 100 mg, and 200 mg as short i.v. infusions in a Cremophor-ethanol vehicle diluted with saline. All administrations were well-tolerated and no compound-related side-effects were observed. Plasma concentrations of dexanabinol were quantitated using a GC/MS/MS technique which provided a limit of quantitation of 100 pg/ml. The elimination of dexanabinol was best fitted to a 3-compartment model with a rapid distribution half-life (< 5 min), an intermediate phase half-life of approximately 90 min, and a slow terminal elimination half-life (approximately 9 h). The pharmacokinetics were linear over the evaluated dose range. The plasma clearance of the drug was high (1,700 ml/min) and the volume of distribution approximately 15 l/kg. These data are similar to those reported for naturally occurring cannabinoids such as delta 9-tetrahydrocannabinol and cannabidiol.     

Disposition of nafcillin in patients with cirrhosis and extrahepatic biliary obstruction

Nafcillin, a semisynthetic penicillin effective against penicillinase-producing staphylococci, is eliminated largely in man via the liver. This study assessed the effect of cirrhosis and extrahepatic biliary obstruction in man on the pharmacokinetics of nafcillin. The plasma clearance of nafcillin controls was 583 +/- 144.2 ml per min (mean +/- SD) and fell strikingly to 291 +/- 147.6 and 163 +/- 56.3 ml per min in patients with cirrhosis and extrahepatic obstruction, respectively (P less than 0.001). In the latter two groups nafcillin excreted in urine increased from about 30 to 50% of administered dose (P less than 0.02), suggesting that renal disease superimposed on hepatic disease would further decrease over-all nafcillin clearance. The depression of nafcillin clearance with hepatobiliary disease did not correlate with any conventional liver laboratory test. The initial volume of distribution of nafcillin (V1) was unaltered but at steady state (Vd()) there was a significant reduction in the distribution volume in the patients with liver disease. Accordingly, the impairment in drug elimination, as assessed by its clearance from plasma, was underestimated by the prolongation of the nafcillin elimination half-life (t1/2(beta)) which was 1.02 +/- 0.20 hr in controls, and 1.23 +/- 0.31 (P greater than 0.05) and 1.73 +/- 0.44 hr (P less than 0.03), respectively, in patients with cirrhosis and extrahepatic obstruction.     

Cyclophosphamide and 4-Hydroxycyclophosphamide/aldophosphamide kinetics in patients receiving high-dose cyclophosphamide chemotherapy

Using a recently developed gas chromatography and mass spectrometry method to determine whole-blood cyclophosphamide (CP) and 4-hydroxycyclophosphamide/aldophosphamide (4-HO-CP/AP) concentrations, we investigated their pharmacokinetics in women receiving CP therapy. Patients (n = 18) received one or two courses of CP: (a) a 90-min i.v. infusion (4 g/m2) followed by a 96-h i.v. infusion (6 g/m2) in combination with high-dose thiotepa; or (b) a 96-h i.v. infusion (6 g/m2) in combination with high-dose thiotepa. Whole-blood exposures to CP [area under the whole blood concentration versus time curve (AUCCP)] and 4-HO-CP/AP (AUC4HOCP) between courses 1 and 2 were compared after normalization to dose (g/m2). A nonproportional increase was observed for the AUCCP between the first course [1112 micrometer. h/g/m2 +/- 14% coefficient of variation (CV)] and the second course (1579 micrometer . h/g/m2 +/- 28% CV) (P < 0.001). In contrast, the AUC4HOCP (27 micrometer . h/g/m2 +/- 25% CV) determined for the first course was 29% higher than the AUC4HOCP (21 micrometer . h/g/m2 +/- 26% CV) for the second course (P < 0.01). The interpatient whole-blood exposures to both CP and 4-HO-CP/AP were remarkably consistent in this patient population with percent CVs ranging from 14 to 28%. Because thiotepa (800 mg/m2) was administered simultaneously with CP during the second course of treatment, possible inhibition of CP metabolism by thiotepa was investigated using human liver microsomes in vitro. IC50 values determined for inhibition of CP metabolism in three individual liver donors ranged from 1.0 to 40 micrometer. However, the clinical relevance of this observation has not been established.     

The effect of asphyxia on the pharmacokinetics of ceftazidime in the term newborn

The multiple-dose pharmacokinetics of ceftazidime (CAZ) (administered twice daily in a 50 mg/kg of body weight i.v. dose) were studied in 10 severely asphyxiated term infants with suspected septicemia on d 3 of life. Nine term infants with suspected septicemia but without asphyxia served as controls. Blood samples were collected from an arterial catheter at 0, 0.5, 1, 2, 4, 8, and 12 h after an i.v. bolus injection. A high performance liquid chromatography method was used to determine CAZ concentrations from serum. CAZ pharmacokinetics followed a one-compartment open model. The GFRs of all infants were simultaneously studied by means of the 24-h continuous inulin infusion technique. Elimination serum half-life (5.86 +/- 1.13 h versus 3.85 +/- 0.40 h) and serum trough concentrations (46 +/- 14 mg/L versus 23 +/- 7 mg/L) of CAZ were significantly (p < 0.001) increased in the asphyxiated newborn, whereas total body clearance of CAZ (128.4 +/- 25.1 mL/h versus 205.7 +/- 55.4 mL/h), CAZ clearance per kg (40.9 +/- 6.1 mL/h/kg versus 60.8 +/- 8.3 mL/h/kg), and the GFR expressed in mL/min (3.14 +/- 0.43 versus 4.73 +/- 0.89) were significantly (p < 0.001) decreased in the asphyxiated newborn. We conclude that twice daily administration of 50 mg/kg of body weight CAZ given to asphyxiated term newborns in the first days of life results in significantly higher serum trough levels in comparison with control infants. The impaired CAZ clearance is a result of a significantly decreased GFR.     

The CAG repeat within the androgen receptor gene and benign prostatic hyperplasia

Thalidomide, a glutamic acid derivative, has recently been shown to inhibit in vitro angiogenesis, the process of formation of new blood vessels. This Phase II study examined the pharmacokinetics of thalidomide in patients with clinically progressive hormone-refractory prostate cancer. Patients (aged 55 to 80 years) were randomized to two different arms, low dose versus high dose. Patients in the low-dose group were given 200 mg of thalidomide and patients in the high-dose group received 200 mg of thalidomide, with subsequent dose escalations to 1200 mg. Serial serum or blood samples were obtained for pharmacokinetic assessment after administration of a single oral dose or multiple daily dosing of thalidomide and were assayed by reversed-phase HPLC. Pharmacokinetic parameters for both the single and multiple dosing were calculated with ADAPT II. A one-compartment model best fit the data. After single dosing, the oral clearance and apparent volume of distribution for the low-dose regimen (n = 13) were 7.41 +/- 2.05 L/h and 66.93 +/- 34.27 L, respectively, whereas for the high-dose regimen (n = 11), these values were 7.21 +/- 2.89 L/h and 165.81 +/- 84.18 L, respectively. The elimination half-lives for the low and high dose were 6.52 +/- 3.81 and 18.25 +/- 14.08 h, respectively. After the multiple dosing of thalidomide, the oral clearance and apparent volume of distribution for the low-dose group (n = 10) were 6.35 +/- 1.64 L/h and 64.63 +/- 23.20 L, respectively, whereas for the high-dose group (n = 11), these values were 7.73 +/- 2.27 L/h and 167.85 +/- 82.08 L, respectively. The elimination half-lives for the low and high dose were 7.08 +/- 1.87 and 16.19 +/- 9.57 h, respectively. For both the single and multiple dosing of thalidomide, the apparent volume of distribution and half-life were significantly higher for the high-dose group than those for the low-dose group. The higher apparent volume of distribution may be attributable to several factors, such as change in absorption, protein binding, etc. A dose-proportional increase in thalidomide steady-state concentrations was seen after multiple daily dosing of thalidomide.     

Functional recognition of in vivo processed self antigen

Of 531 cases of immunoglobulin A nephropathy in the Toronto Glomerulonephritis Registry, 115 were determined by retrospective analysis to have proteinuria > or = 1 g/d. These patients have been followed a minimum of 3 months (range, 3 to 121 months). Monitoring in the registry included routine blood pressure estimates and renal function status by serum creatinine, creatinine clearance, and proteinuria. These patients were grouped and examined retrospectively into three categories (1) hypertensive on angiotensin-converting enzyme (ACE) inhibitor therapy (ACEi), (2) hypertensive on other medication, and (3) no hypertension (NT). Despite comparable renal function abnormalities, the 27 ACEi patients, when compared with the 55 patients receiving other medication, experienced a significantly slower rate of decline in renal function as measured by slope of creatinine clearance (-0.4 mL/min/mo v-1.0 mL/min/mo; P = 0.007), longer time to a loss of one third of baseline creatinine clearance (P = 0.004), and a higher percentage of remission in proteinuria (18.5% v 1.8%; P = 0.003). A subsequent comparison was made between the NT and ACEi groups and, despite a much lower initial serum creatinine, less severe pathology, and a longer observation period in the NT group, both the rate of decline of creatinine clearance (-0.5 mL/min/mo v -0.4 mL/min/mo; P = 0.9) and the percentage of patients progressing to renal failure (21.2% v 18.5; P = 0.8) were not different. The remission rate of proteinuria was superior in the ACEi-treated group compared with the NT group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibition of Salmonella enteritidis by oleuropein in broth and in a model food system

OBJECTIVE: To compare the pharmacokinetics of methylprednisolone in renal transplant recipients on 2 occasions separated by at least 1 month during chronic immunosuppression. DESIGN: A prospective unblinded trial. PATIENTS: Ten renal transplant recipients (aged 25-62 years) evaluated in a public university-affiliated hospital clinic. INTERVENTIONS: All patients received their chronic oral dose of methylprednisolone as a 10-20-minute intravenous infusion during the 2 study periods. MAIN OUTCOME MEASURES: Serum methylprednisolone concentrations were determined by HPLC and were used to generate the pharmacokinetic parameters of the drug. RESULTS: During study 1, which ranged from 1.2 to 24 months posttransplant, the mean +/- SD methylprednisolone dose was 13.2 +/- 6.4 mg. In study 2 (2.5-38.5 mo posttransplant), the mean dose was 10.6 +/- 3 mg. During both study periods, methylprednisolone concentrations exhibited a monoexponential decline. Considerable variability in methylprednisolone clearance was observed between periods in certain patients. Four of the 10 patients demonstrated a reduction in clearance from study 1 to study 2, which ranged from a 28% to a 53% decrease. Two patients exhibited an increase in clearance of 40% and 49%. The mean +/- SD total body clearance in study 1 was 363 +/- 330 mL/min/kg, whereas the mean volume of distribution was 1.18 +/- 0.53 L/kg. The mean elimination rate constant was 0.29 +/- 0.14 h-1, with a mean serum half-life of 2.87 +/- 1.15 h during the first phase. In study 2, the mean methylprednisolone clearance was 261 +/- 150 mL/min/kg (p > 0.05) and the mean volume of distribution was 0.89 +/- 0.31 L/kg (p > 0.05). The mean serum half-life of methylprednisolone was 2.91 +/- 0.60 h (p > 0.05), with the mean elimination rate constant of 0.25 +/- 0.06 h-1 (p > 0.05). CONCLUSIONS: These data demonstrate that intrapatient variability in methylprednisolone clearance exists among certain renal allograft recipients. As a result of the observed variability, patients who are continued on the same dose of methylprednisolone during the posttransplant period of chronic immunosuppression will be subjected to a changing pattern of exogenous glucocorticoid exposure. The impact of these changing patterns requires further prospective evaluation.     

Phase I and pharmacologic study of topotecan in patients with impaired renal function

PURPOSE: To determine the toxicities, pharmacokinetics, and recommended doses of the topoisomerase I inhibitor, topotecan, in patients with varying degrees of renal excretory dysfunction. PATIENTS AND METHODS: Fourteen patients with normal renal function [creatinine clearance (CrCl) > or = 60 mL/min] and 28 patients with varying degrees of renal dysfunction were treated with topotecan 0.4 to 2.0 mg/m2/d as a 30-minute infusion for 5 consecutive days every 3 weeks. Plasma and urine samples were obtained to determine the disposition of topotecan. RESULTS: In patients with mild renal dysfunction (CrCl = 40 to 59 mL/min), dose-limiting hematologic toxicity was observed in three of eight patients receiving topotecan 1.0 mg/m2/d and in two of five patients receiving topotecan 1.5 mg/m2/d. In patients with moderate renal dysfunction (CrCl = 20 to 39 mL/min), dose-limiting hematologic toxicity was observed in three of eight patients who received topotecan 0.5 mg/m2/d, and in two of four patients receiving topotecan 1.0 mg/m2/d; these events were more frequently observed in extensively pretreated patients. Pharmacokinetic analyses showed significant correlations between CrCl and the plasma clearance of both total topotecan [Spearman's correlation coefficient (r2) = 0.65, P = .00001] and topotecan lactone (r2 = 0.65, P = .00003). Mean systemic plasma clearance of total topotecan was significantly reduced in patients with mild (P = .04) and moderate (P = .00006) renal dysfunction. There was no evidence of changes in the pharmacodynamic relationship between topotecan exposure (AUC) and myelotoxicity. CONCLUSION: Dose adjustments are required in patients with moderate, but not mild, renal impairment. For patients with moderate renal dysfunction, the recommended starting dose of topotecan is 0.75 mg/m2/d for 5 days every 3 weeks. Moreover, extensively pretreated patients need further dose reductions.     

Disposition kinetics of cobalt mesoporphyrin in mouse, rat, monkey and dog

1. Radiometric and UV analyses indicated > 95% unchanged cobalt mesoporphyrin (CoMP) in plasma after i.v. or i.m. administration. Blood clearance of CoMP is < 2% of hepatic blood flow in mouse and rat, and < 0.5% of hepatic blood flow in monkey and dog. CoMP elimination t1/2 ranged from 3.1 to 9.9 days in animals after i.v. administration. 2. CoMP is highly (> 99.5%) bound to plasma proteins, but has low affinity for blood cells (Kp < 0.15). The volume of CoMP distribution (Vss < 0.91/kg) is reflective of a distribution to total body water following i.v. administration to mouse, rat, monkey and dog. 3. [14C]CoMP reached highest levels in rat tissue between 1 and 4 days following i.m. injection. Liver, kidney cortex, lymph node, adrenal and spleen demonstrated greatest uptake of radiolabel. Concentration in tissues was readily detectable at 60 days post-dose. 4. CoMP was slowly absorbed after i.m. administration showing dose-dependent pharmacokinetics. The major route of radiolabel elimination was faecal excretion (54% of dose) in rat after an i.m. dose of [14C]CoMP. Approximately 1% of the 14C dose was recovered in the urine over 7 days post-dose. 5. As a polar metalloporphyrin, CoMP has low clearance, restricted tissue distribution and long elimination t1/2 in the laboratory animals.     

Disposition of butadiene epoxides in Sprague-Dawley rats

1,2-Epoxybutene (BMO) and diepoxybutane (BDE) are metabolic products of 1,3-butadiene in rodents. Both BMO and BDE are suspect in the development of tumors in rats and mice. To understand the distribution and elimination of these compounds in the absence of the rate-limiting production from butadiene, the pharmacokinetics of BMO and BDE in blood were determined in adult male Sprague-Dawley rats following intravenous administration. All animals were dually cannulated in these studies. For the BMO studies, rats were dosed with 71, 143, or 286 mumol/kg BMO (n = 3 for each dose group). For the BDE studies, rats were dosed with 523 mumol/kg BDE (n = 3). All animals tolerated the BMO and BDE doses without grossly observable adverse effects. Blood was drawn at predetermined time points and extracted in methylene chloride. BDE and BMO concentrations were quantitated by gas chromatography or gas chromatography/mass spectrometry. The BMO distribution half-lives were short and ranged from 1.4 min at the lowest dose to 1.8 min at the highest dose. Volume of distribution at steady state ranged from 0.53 +/- 0.17 to 0.59 +/- 0.31 l/kg. Systemic clearances ranged from 67 +/- 17 to 114 +/- 20 ml/min per kg. The terminal elimination half-lives were also short and ranged from 5.7 to 8.5 min among the doses. The pharmacokinetic parameters after an i.v. dose of 523 mumol/kg BDE were a distribution half-life of 2.7 min, terminal elimination T1/2 of 14 min, volume of distribution at steady state of 0.73 +/- 0.06 l/kg, and systemic clearance of 76 +/- 8 ml/min per kg. These pharmacokinetic parameters demonstrate the similarity between disposition of the two epoxides in rats, that include a rapid distribution after i.v. administration into a small extravascular body compartment as well as a rapid elimination from blood. These pharmacokinetic data provide useful blood clearance information for assessing the critical physiological and biochemical determinants underlying the disposition of butadiene epoxides.     

Utilization of tyrosine-containing dipeptides and N-acetyl-tyrosine in hepatic failure

The impact of hepatic dysfunction on the elimination and hydrolysis of three potential tyrosine sources for total parenteral nutrition, the dipeptides L-alanyl-L-tyrosine (Ala-Tyr) and glycyl-L-tyrosine (Gly-Tyr), and N-acetyl-L-tyrosine (Nac-Tyr) were evaluated in six patients with hepatic failure (five chronic, one acute) and seven healthy subjects. In controls, whole-body clearance (Cltot) of Ala-Tyr was higher than of Gly-Tyr (3,169 +/- 214 vs. 1,780 +/- 199 mL/kg/min, P < .01), and both exceeded clearance of Nac-Tyr (309 +/- 29 mL/kg/min, P > .01). Both dipeptides were hydrolyzed and released tyrosine immediately. In hepatic failure, elimination and hydrolysis of Ala-Tyr and Gly-Tyr were comparable to controls, but Cltot of Nac-Tyr was reduced (236 +/- 26 mL/kg/min). Neither in controls nor in patients an increase in plasma tyrosine concentration was seen after Nac-Tyr, and the major part of Nac-Tyr infused was lost in urine. The Cltot of tyrosine as evaluated after Ala-Tyr infusion (with the immediate release of tyrosine) was severely reduced in hepatic failure (152.7 +/- 38.4 vs. 484.4 +/- 41.4 mL/kg/min, P < .001) and half-life (kle) was retarded from 14.4 +/- 1.4 to 90.2 +/- 32.2 minutes (P < .03). The authors conclude that acute and chronic hepatic dysfunction does not affect elimination and hydrolysis of the dipeptides Ala-Tyr and Gly-Tyr and the constituent amino acids are released immediately. Nac-Tyr elimination was not grossly affected by hepatic failure, but neither in healthy subjects nor in hepatic failure patients was an increase of tyrosine seen. Both dipeptides but not Nac-Tyr may serve as a tyrosine source in parenteral nutrition. Moreover, by its rapid hydrolysis, the use of Ala-Tyr, for the first time, enables a simple rapid nonisotope evaluation of tyrosine kinetics for assessment of liver function.     

Substance P in the ventral pallidum: projection from the ventral striatum, and electrophysiological and behavioral consequences of pallidal substance P

1. Piroximone was administered orally (p.o.) and intravenously (i.v.) to male Beagle dog. In vitro, piroximone was incubated with dog liver microsomes. 2. Piroximone was metabolized in vivo to five metabolites (1-5) representing approximately 20% of the total administered dose. 3. The parent drug and its metabolites were totally eliminated in urine. 4. Reduced piroximone (piroximole), representing approximately 10% of the administered dose, was identified as the major metabolic product in vivo. 5. In vitro, piroximone was metabolized by dog liver microsomes to isonicotinic acid (1) and piroximole (4), with the same ratio as in vivo (1:4 = 0.2). The Michaelis-Menten parameters were determined for piroximole formation and were: Kmapp = 733 microM and Vmax app = 232 pmol/mg protein/min. 6. Comparison of the pharmacokinetics of piroximone and piroximole revealed that both compounds were very well absorbed (F = 93 +/- 7 and 89 +/- 8% respectively), slightly distributed (Vd app = 0.78 +/- 0.04 and 1.02 +/- 0.09 l/kg p.o., and 0.95 +/- 0.05 and 0.76 +/- 0.13 1/kg i.v. respectively) and excreted into urine to the same extent (UEx = 54.7 +/- 1.2 and 53.2 +/- 12.6% p.o., and 59.1 +/- 5.3 and 51.2 +/- 5.7% i.v. respectively), except that the clearance of piroximone was two-fold higher than that observed for piroximole (ClT = 7.77 +/- 1.35 and 4.12 +/- 0.44 ml/min/kg p.o., and 7.68 +/- 1.25 and 4.06 +/- 0.51 ml/min/kg i.v. respectively).