Population Pharmacokinetic-Pharmacodynamic Model of Oral Fludrocortisone and Intravenous Hydrocortisone in Healthy Volunteers

This study aimed at describing the pharmacokinetics and the concentration-effect relationships of fludrocortisone and hydrocortisone on urinary sodium/potassium excretion in healthy volunteers. This was a placebo-controlled, randomized, double blind, crossover study, of oral fludrocortisone and intravenous hydrocortisone, given alone or in combination, in 12 healthy male volunteers. Nonlinear mixed-effects modeling was used to describe the pharmacokinetics and pharmacokinetic-pharmacodynamic relationships on urinary sodium/potassium ratio for each drug. A one-compartment model was used to describe fludrocortisone and hydrocortisone pharmacokinetics. Mean plasma half-life was 1.40 h (95%CI [0.80;2.10]) for fludrocortisone and 2.10 h (95%CI [1.78;2.40]) for hydrocortisone. Clearance was 40.8 L/h (95%CI [33.6;48]) for fludrocortisone and 30 L/h (95%CI [25.3;34.7]) for hydrocortisone. An indirect response model was used to describe effects on urinary sodium/potassium ratio. Fludrocortisone plasma concentrations showed a wider inter-individual dispersion than hydrocortisone plasma concentrations. Urinary sodium/potassium ratio variability was also higher with fludrocortisone as compared to hydrocortisone. The plasma concentration of drug producing 50% of maximal inhibition of urinary sodium/potassium (IC₅₀) was about 200 times lower for fludrocortisone (0.08 μg/L, 95%CI [0.035;0.125]) than for hydrocortisone (16.7 μg/L, 95%CI [10.5;22.9]). Simulations showed that a 4-time per day administration regimen allow to achieve steady fludrocortisone plasma concentrations with stable decrease in urinary sodium/potassium ratio after the second administration of fludrocortisone. Fludrocortisone and hydrocortisone have short and similar plasma elimination half-lives in healthy subjects. Fludrocortisone plasma concentrations and effect on urinary sodium/potassium ratio had a higher inter-individual variability as compared to hydrocortisone. The administration regimen of fludrocortisone should be reconsidered.     

In vivo fate of a behaviorally active ACTH 4-9 analog in rats after systemic administration.

In vivo fate of a threefold substituted ACTH 4-9 analog with a markedly potentiated behavioral activity, 4-Met(O2), 8-D-Lys, 9-Phe-ACTH 4-9, was investigated. The radioactive labeled [7-3H-Phe] ACTH 4-9 analog was administered IV, SC and orally in a dose of approximately 40 mug. Plasma concentrations of total radioactivity and intact peptide were determined at various periods after administration in urethane anesthetized rats. Oral administration was also performed with conscious animals. Maximal plasma concentrations were found 8 min after SC injection. After oral administration in anesthetized rats maximal plasma levels were reached 8 hr after administration; in conscious animals this took 4 hr. The initial volume of distribution was 5.9% of body weight and the initial half-life (t1/2) for intact peptide 4 min. Shortly after IV and SC administration relatively high and stable plasma levels of intact peptide were obtained, reflecting metabolic stability. This stability was also apparent from the metabolite patterns, which were determined in trichloroacetic acid extracts of plasma and brain by paperchromatography and paperelectrophoresis. The plasma profiles indicated increased stability of the labile 8Lys-9Phe bond by the introduction of an 8D-Lys residue in the peptide analog. Enzymatic attack of the analog took place predominantly at 6His-7Phe and 7Phe-8D-Lys. Formation of tritiated water occcurred in brain and the gastro-intestinal tract and was considerable; proteolysis in these compartments was higher than in plasma. High uptake of radioactivity was found in the kidney, but urinary excretion was low during the first 30 min. Uptake in brain was low and paralleled uptake in cerebrospinal fluid. Intact peptide concentrations/g fresh tissue were in the order of 10(-5)-10(-4) times the administered dose for all three routes.     

Pharmacokinetics of tranexamic acid in patients with ulcerative colitis and in healthy volunteers after the single instillation of 2 g rectally.

Topically applied antifibrinolytic drugs may be of value in the control of bleeding in active ulcerative colitis. Any impairment of systemic fibrinolysis in this condition, however, is potentially harmful. Since pharmacokinetic data after the rectal administration of tranexamic acid are non-existent, plasma concentration and recovery in the urine were recorded after a single dose of 2 g tranexamic acid given rectally to five patients with ulcerative colitis and to five healthy volunteers. The median area under the curve was, for the volunteers, 7.64 mg/L x hr (range: 4.43-11.56) and, for the patients, 13.84 mg/L x hr (range: 9.32-50.22) (P less than .05). The median 24-hour recovery in the urine was 0.8% (0.3-1.1) and 2.7% (1.1-4.0), respectively (P less than .05). The median peak plasma concentration was, for the volunteers, 0.40 mg/L (range: 0.20-0.69) 6 hours after administration and, for the patients, 1.10 mg/L (range: 0.53-2.90) 5 hours after administration (P less than .05). The plasma concentrations and recovery in the urine that were observed in the patients and volunteers were low compared with those seen after oral intake of the same dose. The plasma concentrations did not reach levels that were considered liable to impair systemic fibrinolysis.     

Clinical pharmacokinetics of carboplatin

The pharmacokinetics of carboplatin were investigated in cancer patients after single, IV infusion doses of 75, 150, 247.5, 300, 375, and 450 mg/m2. Total plasma and urine platinum and plasma ultrafilterable platinum concentrations were determined by atomic absorption spectrometry. Carboplatin was analyzed in plasma by a specific high-performance liquid chromatography (HPLC) procedure. Total plasma platinum, which represented free carboplatin, protein-bound platinum and metabolites, declined triexponentially; plasma half-lives (t1/2 lambda 1, 0.2 to 0.4 hr; t1/2 lambda 2, 1.3 to 1.7 hr; t1/2 lambda 3, 22 to 40 hr) and total body clearance (CLTB 2.8 +/- 0.5 L/m2/hr) were dose independent. Maximum plasma concentrations (Cmax) and area under the plasma concentration time curve (AUC) increased proportionally with dose. Plasma ultrafilterable platinum and carboplatin concentrations at doses of 375 and 450 mg/m2 declined in a biphasic manner. Plasma carboplatin elimination (t1/2 lambda 1, 0.50 hr; t1/2 lambda 2, 2.2 hr) and CLTB (4.4 to 5.6 L/m2/hr) were also independent of dose; AUC and Cmax increased proportionally to dose. Plasma free platinum was essentially all carboplatin for 8 or 12 hours after administration. Carboplatin did not bind to plasma protein in vitro but did degrade (t1/2-26 hours) to yield a reactive intermediate that bound rapidly and irreversibly to protein. The long terminal elimination half-life of plasma platinum was associated with irreversible binding of a platinum metabonate to plasma protein. The urinary excretion of platinum (0 to 24 hours) accounted for 58 to 72% of doses in 12 to 24 hours. The remainder of the dose is slowly excreted. The pharmacokinetics, in vivo stability, protein binding, and elimination of carboplatin are distinct from the first-generation analog cisplatin.     

AICA-riboside: safety, tolerance, and pharmacokinetics of a novel adenosine-regulating agent

AICA-riboside (5-amino-4-imidazole carboxamide ribonucleoside) is a novel adenosine-regulating agent that is currently being investigated for the treatment of ischemic heart disease. In a placebo-controlled, double-blind study in healthy men, we evaluated the safety and kinetics of the drug after oral and IV administration of 10, 25, 50, and 100 mg/kg doses. At each dose level, four subjects received active drug and two subjects received placebo with a 1-week wash-out period between the IV and oral doses. The drug was well tolerated at all dose levels with only mild and transient side effects reported in some instances by the subjects who received placebo and those patients who received the drug. The post-infusion plasma concentrations of AICA-riboside declined rapidly in a biphasic fashion, and the terminal elimination phase had a harmonic mean t1/2 beta of 1.4 hours. Total plasma clearance (CL), mean residence time (MRTIV), and volume of distribution at steady-state (VSS) were 2.5 L/hr/kg, 0.7 hr, and 1.6 L/kg, respectively. The drug was not protein bound, and there was rapid uptake and phosphorylation in RBCs to its 5'-monophosphate nucleotide. Renal clearance (CLR) was 0.2 L/hr/kg with only 8% of the IV dose excreted in the urine as intact AICA-riboside. Although there was a trend towards a decrease in CL with increasing dose, there were no significant differences (P greater than .05) in the mean estimates of t1/2 beta, CL, CLR, MRTIV and VSS associated with dose. The drug was poorly bioavailable (less than 5%) when administered orally in solution.     

Pharmacokinetics and pharmacodynamics of intravenous cibenzoline in normal volunteers

The pharmacokinetics of intravenous (IV) cibenzoline were studied in six healthy male volunteers ranging in age from 51 to 78 years. The subjects received intravenous (IV) cibenzoline 100 mg over 20 minutes, and plasma and urine specimens were collected for 48 hours. Cibenzoline plasma concentrations at the end of the infusion ranged from 730 to 1,420 ng/mL and exhibited triexponential decline thereafter. The following mean model independent pharmacokinetic parameters were calculated from the plasma and urine concentration data: terminal half-life, 9.8 hours (range, 8.5-11.9); plasma clearance, 523 mL/min (range, 387-687); volume of distribution, 445 L (range, 328-506); and renal clearance, 289 mL/min (range, 202-334). Approximately 31% to 59% of the dose was recovered unchanged in the urine in 48 hours. A triexponential pharmacokinetic equation with zero order input was used to curve fit the plasma and urine data, and the model-dependent parameters agreed well with the model-independent estimates. A hysteresis loop was observed in the relationship between cibenzoline plasma concentration and QRS prolongation, indicating an initial lag between plasma concentration and effect after IV administration. Based on these results, the following preliminary dosing regimen was proposed to rapidly achieve and maintain therapeutic plasma concentrations equal to or slightly greater than 200-400 ng/mL: 0.25 mg/kg/min IV bolus over one minute followed by 1-1.5 mg/kg/hr for one hour and 0.2-0.4 mg/kg/hr for long-term infusion.     

Pharmacokinetic Studies of Methotrexate in Plasma and Synovial Fluid Following IV Bolus and Topical Routes of Administration in Dogs

Purpose. The pharmacokinetic properties of methotrexate (MTX) in the plasma and synovial fluid (SF) after bolus IV and topical administration were studied in dogs to assess the feasibility of topical delivery of MTX for the treatment of rheumatoid arthritis. Methods. A MTX gel in Poloxamer 407 containing an absorption enhancer was formulated and topically applied on the elbow and stifle joints of dogs. SF was collected by inserting a needle with syringe into the joint space. Drug concentrations in the plasma, SF and muscle tissues were determined using a HPLC method with fluorimetric detection. Results. Peak MTX concentrations in SF occurrred at 38 ± 5 min following bolus IV dose, indicating the presence of a substantial diffusion barrier between the plasma and SF. The plasma/SF concentration ratios of 1.16 ± 0.25 were maintained after the attainment of distribution equilibrium between the two compartments. The t1/2 values in the plasma (11.2 ± 1.2 hr) and SF (12.7 ± 3.7 hr) were similar during the elimination phase, while the MRT in SF (3.24 ± 0.21 hr) was longer than that in plasma (2.56 ± 0.20 hr), probably due to the slow distribution of MTX to SF. After topical dose, MTX concentrations in plasma reached the steady state at ~4 hr, lasting for ~20 hr.The bioavailability of MTX from the gel was 11.8 ± 3.3% of the applied dose, but muscle tissues beneath the gel application site had significantly higher levels of MTX than untreated muscle tissues. There was no statistical difference in SF concentrations of MTX between drug treated and untreated joints 24 hr after topical dose. Conclusions. Topical delivery of MTX in a hydrophilic gel achieved a sustained C/t profile in plasma and higher drug levels in muscle tissues underneath the dosing site, implicating the potential therapeutic value of the topical formulation. Methods. A MTX gel in Poloxamer 407 containing an absorption enhancer was formulated and topically applied on the elbow and stifle joints of dogs. SF was collected by inserting a needle with syringe into the joint space. Drug concentrations in the plasma, SF and muscle tissues were determined using a HPLC method with fluorimetric detection. Results. Peak MTX concentrations in SF occurrred at 38 ± 5 min following bolus IV dose, indicating the presence of a substantial diffusion barrier between the plasma and SF. The plasma/SF concentration ratios of 1.16 ± 0.25 were maintained after the attainment of distribution equilibrium between the two compartments. The t1/2 values in the plasma (11.2 ± 1.2 hr) and SF (12.7 ± 3.7 hr) were similar during the elimination phase, while the MRT in SF (3.24 ± 0.21 hr) was longer than that in plasma (2.56 ± 0.20 hr), probably due to the slow distribution of MTX to SF. After topical dose, MTX concentrations in plasma reached the steady state at ~4 hr, lasting for ~20 hr.The bioavailability of MTX from the gel was 11.8 ± 3.3% of the applied dose, but muscle tissues beneath the gel application site had significantly higher levels of MTX than untreated muscle tissues. There was no statistical difference in SF concentrations of MTX between drug treated and untreated joints 24 hr after topical dose. Conclusions. Topical delivery of MTX in a hydrophilic gel achieved a sustained C/t profile in plasma and higher drug levels in muscle tissues underneath the dosing site, implicating the potential therapeutic value of the topical formulation.     

The pharmacokinetics and pharmacodynamics of lisuride in healthy volunteers after intravenous,intramuscular, and subcutaneous injection

Summary The plasma concentration of lisuride and prolactin have been measured in twelve healthy male volunteers after IV, IM or SC injection of 25 g lisuride hydrogen maleate as an aqueous solution.After IV administration the plasma lisuride fell in two phases with half-lives of 14 min and 1.5 h. Total clearance was 13 ml·min^–1·kg^–1. After IM and SC injection the plasma concentrations peaked at 12 to 15 min and the profiles were similar to that found after IV administration. The systemic availabilities were 90% and 94%, respectively. Prolactin concentrations were reduced by a maximum of 60% relative to the normal circadian rhythm after all three routes of administration.The treatments were well tolerated, the only adverse reactions reported by some of the volunteers being mild, transient dizziness, tiredness, and nausea.     

Comparative Pharmacokinetics of Methylprednisolone Phosphate and Hemisuccinate in High Doses

The pharmacokinetics of methylprednisolone and two methylprednisolone esters, the phosphate and the hemisuccinate, were investigated after intravenous administration of the esters to 12 healthy male subjects in two different doses (250 and 1000 mg). Methylprednisolone was formed more rapidly from phosphate than from hemisuccinate. During the first 30 min methylprednisolone levels were three to four times higher after phosphate administration than after hemisuccinate. The mean residence time of the hemisuccinate was significantly longer and the total-body clearance lower than those of the phosphate. Whereas very little of the phosphate (mean, 1.7%) was eliminated unchanged into the urine, there were significant amounts of hemisuccinate (mean, 14.7%) excreted renally and therefore not bioavailable. Methylprednisolone saliva levels paralleled plasma levels; the average saliva/plasma ratio was 0.22. Neither phosphate nor hemisuccinate could be detected in saliva. An average of 7.2% of the administered dose was eliminated in the form of methylprednisolone in urine. Renal clearance was 24 ml/min and not dose or prodrug dependent. For both doses endogenous hydrocortisone levels were lowered after 24 hr. For the 1000-mg dose the depression was still significant after 48 hr. The results indicate that methylprednisolone phosphate results in a faster and more efficient conversion to its active form, methylprednisolone, than methylprednisolone hemisuccinate.     

Pharmacokinetics of Cefixime in Children with Urinary Tract Infections after a Single Oral Dose

Abstract: The pharmacokinetics of cefixime, a third-generation broad-spectrum cephalosporin, were determined following administration of a 8 mg/kg single oral dose of cefixime suspension to six children with urinary tract infections, ages from 6 to 13 years and weights from 17 to 60 kg. Blood samples for determination of plasma cefixime concentrations were obtained for up to 12 hr and complete urine collections were obtained for urinary excretion of unchanged parent drug for up to 24 hr after administration. Plasma and urine concentrations of cefixime were determined using a reversed phase HPLC assay and pertinent pharmacokinetic parameters were estimated by model-independent standard methods. Mean peak plasma concentration was 4.04 ug/ml and was reached after 3.2 hr. The mean area under the plasma concentration-time curve was 33.07 ug.hr/ml and the mean elimination half-life was 3.91 hr. The mean apparent total clearance was 4.74 ml/min./kg and about 15% of the dose administered was recovered unchanged in urine. In conclusion, the estimated pharmacokinetic values of cefixime were comparable to those observed in healthy adult subjects based on equivalent mg/ kg doses. Plasma and urine concentrations of the drug were well above the reported minimal plasma and urinary concentrations for most common urinary tract pathogens for up to 12 and 24 hr after administration, respectively.     

HPLC测定结肠黏膜中氢化可的松的浓度及其局部作用机理初探

目的：建立检测结肠黏膜中氢化可的松(HD)浓度的方法，并初步探讨HD灌肠治疗溃疡性结肠炎(UC)的局部作用机理。方法：采用HPLC测定HD灌肠后不同时间血及肠黏膜活检组织中的药物浓度，并由药动学软件算出相应药动学参数。结果：检测了两例患者在使用HD灌肠剂后的6个不同时点，血及肠黏膜组织中HD的浓度，并算出相应药动学参数。HD在黏膜中Tmax=1．16h，T1／2=0．84h；在血中Tmax=0.25h，T1／2=11．23。结论：HD局部灌肠可能同时具有局部和全身作用。     

Optimization of sampling time for cyclosporine monitoring in transplant patients.

Cyclosporine (CsA) dosing is based on CsA plasma or blood concentrations measured 12 to 24 hours after drug administration (trough levels). This study evaluated the relationship between the timing of CsA concentrations and subsequent pharmacokinetic parameters to predict an optimal sampling period. Plasma samples were obtained from 22 patients before their morning dose of CsA and at 2, 4, 6, 8, 10, and 12 hours after the dose on the 7th and on the 21st day after heart transplantation. The plasma samples were assayed by both HPLC and FPIA. The Cmax for CsA was achieved over a period ranging from 2 to 6 hours (mean/median = 4.7/4.0) during the day 7 and the day 21 studies. The mean (+/- SD) half-life was 3.2 (1.0) hours on day 7 and 2.9 (1.1) hours on day 21, (P > 0.05); the mean apparent oral clearance was 276 (117) L/hr on the day 7 and 269 (209) L/hr on day 21, (P > 0.05). When CsA plasma concentration by either FPIA and HPLC was monitored, the drug concentration best correlated with AUC was found to correspond to the plasma samples taken 4 to 8 hours after drug administration. The authors conclude that through blood sampling for therapeutic drug monitoring of CsA is not optimal, and that further studies are necessary to correlate concentration monitoring during the dosing interval with pharmacologic and toxicologic parameters.     

Elimination of Ascorbic Acid After High‐Dose Infusion in Prostate Cancer Patients: A Pharmacokinetic Evaluation

Treatment with high‐dose intravenous (IV) ascorbic acid (AA) is used in complementary and alternative medicine for various conditions including cancer. Cytotoxicity to cancer cell lines has been observed with millimolar concentrations of AA. Little is known about the pharmacokinetics of high‐dose IV AA. The purpose of this study was to assess the basic kinetic variables in human beings over a relevant AA dosing interval for proper design of future clinical trials. Ten patients with metastatic prostate cancer were treated for 4 weeks with fixed AA doses of 5, 30 and 60 g. AA was measured consecutively in plasma and indicated first‐order elimination kinetics throughout the dosing range with supra‐physiological concentrations. The target dose of 60 g AA IV produced a peak plasma AA concentration of 20.3 mM. Elimination half‐life was 1.87 hr (mean, S.D. ± 0.40), volume of distribution 0.19 L/kg (S.D. ±0.05) and clearance rate 6.02 L/hr (100 mL/min). No differences in pharmacokinetic parameters were observed between weeks/doses. A relatively fast first‐order elimination with half‐life of about 2 hr makes it impossible to maintain AA concentrations in the potential cytotoxic range after infusion stop in prostate cancer patients with normal kidney function. We propose a regimen with a bolus loading followed by a maintenance infusion based on the calculated clearance.     

Fate of Erythritol after Single Oral Administration to Rats and Dogs

The absorption and distribution of radiolabeled erythritol were studied in Wistar rats and beagle dogs after a single oral administration in doses ranging from 0.125 to 2.0 g erythritol/kg body wt. Erythritol concentrations in blood and plasma of rats reached their maxima 1 hr after administration and then declined biexponentially. In the blood and plasma of dogs, the highest concentrations occurred after 1/2 hr followed by a similar decline. Blood plasma distribution ratios and plasma protein binding ratios increased as blood plasma levels declined. At 120 hr after administration, 95.68 ± 2.25% of the radioactivity had been excreted in the urine of dogs and 92.70 ± 0.44% in the urine of rats; 0.33 ± 0.05% had been excreted in the feces of dogs and 1.19 ± 0.09% in the feces of rats; 1.17 ± 0.04% had been excreted in expired air from dogs and 4.80 ± 0.32% in expired air from rats. The results demonstrate that erythritol is rapidly absorbed and excreted, principally through the urinary pathway.     

Pharmacokinetics and rectal bioavailability of hydrocortisone acetate.

The pharmacokinetics and bioavailability of hydrocortisone after rectal administration of a hydrocortisone acetate foam was determined. Endogenous hydrocortisone was suppressed by dexamethasone administration. Plasma levels were compared with those observed after iv and oral administration. Only a very small part of the rectal dose (100 mg) was absorbed; the mean absolute bioavailability was 2%. There was substantial intersubject variability. Maximum hydrocortisone levels were reached after 2 h and averaged 35 ng/mL. These levels were 10-fold lower than those obtained after oral administration of a fivefold lower dose (20 mg) of hydrocortisone in the same subjects.     

Radioimmunoassay of flurazepam in human plasma

A radioimmunoassay for the determination of the hypnotic flurazepam in plasma was developed. Plasma levels of intact flurazepam were measured following oral administration of therapeutic doses to humans. The procedure employs an antiserum obtained from a rabbit immunized with 3-hemisuccinyloxyfluorazepam covalently coupled to bovine serum albumin and tritium-labeled flurazepam as the radioligand. Assay specificity was achieved by chromatographic isolation of flurazepam from plasma extracts on Sephadex LH-20 prior to analysis. The method has a sensitivity limit of 0.1 ng of flurazepam/ml using a 1-ml plasma sample, and the intra- and interassay coefficients of variation did not exceed 9% over a range of 0.1-5 ng/ml. In eight subjects who received a single 30-mg dose of flurazepam, peak plasma concentrations of 0.5-3.0 ng of intact drug/ml were reached after 0.5-1 hr, except in one subject where the peak occurred at 4 hr. The plasma concentrations of flurazepam declined with a harmonic mean apparent half-life of 2.3 hr.     

Cobalt-induced alterations in plasma proteins, proteases and kinin system of the rat

Rats receiving an injection of cobalt (Co) showed marked changes in plasma kininogen (Brady kininogen, BKG) levels, and alterations in arginine-esterase and bradykininase activity. A significant increase in BKG concentrations was seen at 4 and 24 hr after Co treatment, with maximum titers occurring 4 hr after treatment. Plasma kallikrein activity was significantly increased between 1 and 24 hr after Co treatment. Co initiated a decrease in plasma kininase activity, with minimum activity occurring 8 hr after treatment. Plasma protease showed peak activity approximately 8 hr after Co administration. However, Co added in vitro failed to enhance the proteolytic activity of rat plasma from normal as well as cobalt-treated rats. Plasma protein concentrations were significantly increased above control levels at 18 and 24 hr after cobalt treatment. These observations would seem to suggest that Co. which is known to initiate a state of histotoxic (tissue) hypoxia, might be triggering a mechanism(s) responsible for the changes seen in the plasma.     

Disposition of the novel serotonin agonist, LY228729, in monkeys and rats.

The disposition of a novel 5HT-1a agonist, LY228729, was studied in rats after oral administration and in monkeys after both i.v. and oral administration of a radiolabeled drug. Plasma concentrations of LY228729 declined with a half-life of 2.3 and 1.5 hr in monkeys after oral dosing and i.v. administration, respectively, and 1.9 hr in rats dosed orally. Peak plasma concentrations of the N-despropyl metabolite were greater than the parent drug following oral administration in both rats and monkeys and declined with a half-life of 3.2-3.5 hr. Plasma levels of total radioactivity rapidly exceeded that of the parent drug in both species. Radioactivity was eliminated more slowly, with terminal half-lives of 39.4 hr in the monkey and 48.6 hr in the rat. The parent drug and its despropyl metabolite accounted for only a small percentage of the total radioactivity in the plasma. Following i.v. and oral administration, radioactivity was eliminated predominantly in the urine of monkeys, but was distributed evenly between the urine and feces of rats. Parent drug and the N-despropyl metabolite were the major products in rat urine. In the monkey, the major metabolite was an uncharacterized polar compound.     

Coadministration of milk thistle and indinavir in healthy subjects

STUDY OBJECTIVE: To determine if milk thistle (silymarin) alters the pharmacokinetics of indinavir. DESIGN: Sequential crossover trial. SETTING: General clinical research center. SUBJECTS: Ten healthy subjects. INTERVENTION: Indinavir 800 mg 3 times/day was given for four doses on days 1 and 2. Silymarin 160 mg 3 times/day was given on days 3-15. On day 16 and for one dose on day 17, both drugs were given at the same dosages. MEASUREMENTS AND MAIN RESULTS: Indinavir's pharmacokinetic parameters were evaluated at steady state both before and after administration of 14 days of silymarin. Blood samples were collected -0.25, 0.5, 1, 2, 3, 4, and 5 hours after indinavir dosing and assayed by high-performance liquid chromatography. The final pharmacokinetic model had first-order absorption after a lag time, and two compartments with first-order elimination from the central compartment. When given alone and combined with silymarin, respectively, the geometric mean (95% confidence interval [CI]) steady-state indinavir area under the plasma concentration-time curve was 20.7 hr x mg/L (15.3-28.2 hr x mg/L) and 19.4 hr x mg/L (15.8-23.6 hr x mg/L) and the trough plasma concentration was 0.340 mg/L (0.232-0.497 mg/L) and 0.232 mg/L (0.129-0.419 mg/L). CONCLUSION: Silymarin has no apparent effect on indinavir plasma concentrations.     

Pharmacokinetics of rec-hirudin in healthy volunteers after intravenous administration

The pharmacokinetics of recombinant hirudin (rec-hirudin, Ciba-Geigy, CGP 39 393) in healthy volunteers after iv administration was investigated on the basis of the data from five different studies. A total of 77 plasma profiles following a single iv bolus dose of either 0.1, 0.3, 0.5, or 1 mg/kg of rec-hirudin was used for the evaulation. Plasma concentrations and especially AUC were proportional to the dose. Kinetics of rec-hirudin after a bolus iv injection were best described by a three-compartment open model. Mean apparent terminal half-life was 2.8 hr and the total clearance 0.138 L/hr per kg.