Pharmacokinetics of palonosetron in combination with aprepitant in healthy volunteers

BACKGROUND: Palonosetron is a second-generation 5-HT(3) receptor antagonist with a prolonged duration of action and higher receptor binding affinity than first-generation agents (ondansetron, granisetron, and dolasetron). Aprepitant is a selective antagonist of substance P/neurokinin 1 that augments the benefit of 5-HT(3) receptor antagonists in the prevention of chemotherapy-induced nausea and vomiting. METHODS: This randomized, open-label, two-way, crossover trial was designed to evaluate the effect of oral aprepitant on the pharmacokinetics and safety of a single intravenous (IV) dose of palonosetron in 12 healthy subjects. Treatment A consisted of a single IV bolus dose of palonosetron 0.25mg on day 1. Treatment B added oral aprepitant 125 mg on day 1 (30 minutes prior to palonosetron) and 80 mg on days 2 and 3. Blood for pharmacokinetic evaluations was collected through 168 hours after palonosetron administration on days 1 and 15; safety was monitored through day 22. RESULTS: Mean plasma concentration-time plots for palonosetron were virtually identical for palonosetron administered alone or with concomitant aprepitant. The ratio of geometric least-square mean values (with:without aprepitant) for C(max) was 98.6% (90% confidence interval [CI]: 61.8-157%), and for AUC(0-infinity) the ratio was 101% (90% CI: 85.6-119%). With and without aprepitant coadministration, respectively, mean plasma elimination half-life was 40 hours and 43 hours (difference: -3.0 hours; p = 0.348), mean total body clearance was 130 mL/min and 136 mL/min (difference: -5.6 mL/min; p = 0.735), and mean volume of distribution at steady-state was 410.9 L and 442.3 L (difference: -31.4 L; p = 0.463). Palonosetron alone and the palonosetron/aprepitant regimen were well tolerated. CONCLUSION: These results indicate no significant differences in pharmacokinetic parameters for palonosetron between the two treatments, and suggest that palonosetron can be safely coadministered with aprepitant with no alterations in the expected safety profile and no dosage adjustment necessary.     

Palonosetron

Palonosetron is a potent and highly selective serotonin 5-HT(3) receptor antagonist that has been evaluated for the prevention of chemotherapy-induced nausea and vomiting. black triangle Intravenously administered palonosetron has a linear pharmacokinetic profile, with a long terminal elimination half-life ( approximate, equals 40 hours) and moderate (62%) plasma protein binding. In two randomised, double-blind trials in 1132 cancer patients receiving moderately emetogenic chemotherapy, intravenous palonosetron 0.25 mg was more effective than intravenous ondansetron 32 mg in producing a complete response (no emesis, no use of rescue medication) during acute (0-24 hours) or delayed (24-120 hours) phases, and similar to intravenous dolasetron 100 mg in acute, but more effective in delayed phase. Palonosetron 0.75 mg was similar to ondansetron (acute and delayed phase) or dolasetron (acute phase), but more effective than dolasetron in delayed phase. In patients receiving highly emetogenic chemotherapy (n = 667), the complete response rates during acute and delayed phases with intravenous palonosetron (0.25 or 0.75 mg) were similar to those seen in intravenous ondansetron 32 mg recipients in a randomised, double-blind trial. Intravenous palonosetron was generally well tolerated in clinical trials, with few adverse events being treatment related. Palonosetron had no significant effect on the corrected QT interval or laboratory parameters.     

Pharmacokinetics and pharmacodynamics of tenecteplase: results from a phase II study in patients with acute myocardial infarction

Tenecteplase is a site-specific engineered tissue plasminogen activator (t-PA) variant that can be administered as a single intravenous bolus injection because of its slower plasma clearance. The objective of this study was to investigate the dose-ranging pharmacokinetics and pharmacodynamics of intravenous bolus tenecteplase compared with intravenous alteplase recombinant t-PA in patients with acute myocardial infarction. A total of 103 patients received intravenous bolus doses of 30, 40, or 50 mg tenecteplase, and 56 patients received 100 mg rt-PA as the accelerated 90-minute infusion regimen in this randomized, open-label study. Tenecteplase and r-tPA plasma concentrations were measured for 6 hours. Tenecteplase exhibited biphasic elimination from the plasma with a mean initial half-life of 22 minutes and a mean terminal half-life of 115 minutes. The mean plasma clearance was 105 mL/min and did not depend on tenecteplase dose over the dose range studied. In comparison, rt-PA has a fourfold faster plasma clearance. Pharmacokinetic-pharmacodynamic evaluation showed that a dose of approximately 0.5 mg/kg results in a plasma AUC value that provides a TIMI 3 flow at 90 minutes that is comparable to that reported with accelerated r-tPA. In conclusion, tenecteplase has a fourfold slower plasma clearance compared with rt-PA, allowing dosing as an i.v. bolus injection. Weight-adjusted dosing of tenecteplase may optimize the therapeutic regimen of tenecteplase.     

Multiple-dose pharmacokinetics and safety of bevirimat, a novel inhibitor of HIV maturation, in healthy volunteers

BACKGROUND AND OBJECTIVE: Bevirimat [3-O-(3',3'-dimethylsuccinyl)-betulinic acid] is a novel inhibitor of HIV-1 maturation. This study was performed to investigate the pharmacokinetics and safety of bevirimat during repeated dosing in healthy volunteers. SUBJECTS AND METHODS: The study was a 10-day, randomised, double-blind, placebo-controlled, dose escalation study. A total of 48 healthy male volunteers, aged 19-54 years, took part in the study. Treatment was administered for 10 days in six escalating dose cohorts (n = 8 in each cohort; 6 bevirimat, 2 placebo). The doses of bevirimat given in each successive cohort were 25 mg, 50 mg, 75 mg (with 150 mg loading dose), 100 mg, 150 mg and 200mg. Safety follow-up was performed 28 days after the first dose. PHARMACOKINETIC AND STATISTICAL ANALYSIS: Plasma bevirimat levels were measured from blood samples collected pre-dose on days 1-10 and then at approximately 48-hour intervals until 21 days after dosing started. On days 1 and 10, further blood samples were obtained at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours after dosing. Urine samples were collected in the morning on days 1, 5 and 11 and at the end of the study for the measurement of cortisol and 6beta-hydroxycortisol. The pharmacokinetic parameters of bevirimat were estimated using non-compartmental methods. MAIN OUTCOME MEASURE: Dose proportionality of exposure to bevirimat, assessed by the maximum plasma concentration and the area under the plasma concentration-time curve. RESULTS: The mean terminal elimination half-life of bevirimat ranged from 56.3 to 69.5 hours, and the mean clearance ranged from 173.9 to 185.8 mL/hour. Bevirimat showed approximately 4-fold greater accumulation on day 10 compared with day 1, and the degree of accumulation was similar with all doses. Maximum plasma concentrations ranged from 8 to 58 microg/mL at day 10. Testing for dose-proportionality showed that exposure to bevirimat was proportional to the dose, both after a single dose and after repeat dosing for 10 days. Measurement of the urinary 6beta-hydroxycortisol/cortisol ratio indicated that bevirimat did not affect cytochrome P450 3A activity. Repeated dosing with bevirimat for 10 days was well tolerated. There was no increase in adverse events observed for bevirimat compared with placebo, and no serious adverse events occurred. No clinically relevant changes in vital signs, physical examination or clinical laboratory evaluations were observed. CONCLUSIONS: Bevirimat shows dose-proportional pharmacokinetics during repeated dosing for 10 days. Its accumulation is approximately 4-fold greater on day 10 compared with day 1. Repeated dosing with bevirimat is well tolerated. These properties make bevirimat potentially suitable for inclusion in highly active antiretroviral therapy regimens.     

Elimination of brotizolam in elderly patients after multiple doses

Summary Plasma brotizolam levels were measured in 5 elderly patients given 0.25 mg daily. The half-life of brotizolam elimination was 6.0 h after a single dose and 6.9 h after continuous administration for 3 weeks. The brotizolam concentration in plasma 2 h after the dose was 3.5 and 3.4 ng/ml, respectively, on the first and last days of the study. Brotizolam levels measured several times during the study 10 h after dosing were between 1.2 and 1.8 ng/ml.Thus, administration of brotizolam 0.25 mg/d to elderly patients for 3 weeks led neither to its accumulation nor to faster elimination. The half-life of brotizolam elimination in elderly patients was in the upper range of that found in young volunteers.Preliminary results were reported at the Brotizolam Symposium, Bad Schachen, FRG, 1982. (Br J Clin Pharmacol (1983) 16 [Suppl 2]: 201 S–442 S)     

Clinical pharmacology of multiple doses of lasofoxifene in postmenopausal women

Lasofoxifene, a next-generation selective estrogen receptor modulator, is undergoing phase 3 clinical development for osteoporosis. This study evaluated daily lasofoxifene for 14 days in healthy postmenopausal women. A loading dose of 5 times the daily dose was followed by daily doses of 0.01 mg (n = 8), 0.03 mg (n =8), 0.1 mg(n = 16), 0.3 mg (n =9), 1 mg (n = 8), or placebo (n = 16). Samples were collected for pharmacokinetic and pharmacodynamic assessments. Lasofoxifene was well tolerated; study drug-associated adverse events were mild and unrelated to dose. There was a predictable increase in plasma concentrations of lasofoxifene with dose. Pharmacokinetic parameters included mean half-life of 165 hours, mean area under the plasma concentration-time curve from time 0 to 24 hours ranging from 1.67 ng x h/mL to 137 ng x h/mL, and mean maximum observed plasma concentration ranging from 0.09 ng/mL to 6.43 ng/mL. Lasofoxifene partially suppressed luteinizing hormone, follicle-stimulating hormone, low-density lipoprotein, and N-telopeptide.     

Disposition of amiodarone in rats after single and multiple intra-peritoneal doses.

The pharmacokinetics of amiodarone was studied after single and multiple dosing in two groups of male Wistar and Albino rats. The first group (40 rats) received a single intraperitoneal (i.p.) dose of amiodarone (100 mg/kg) and 4 rats sacrificed 1, 2, 4, 6, 12, 18, 24, 36, 48 and 72 hours post dosing. The second group (42 rats) received amiodarone (50 mg/kg, i.p., daily) for 5 days a week for 5 weeks and 6 rats were sacrificed at 1, 2, 3, 4, 5, 6 and 8 weeks. Rats of both group were sampled for blood, heart, lung and fat and the concentrations of amiodarone in these samples were determined using. The elimination of amiodarone from plasma after single dose followed a biphasic pattern with a terminal half-life of 54.7 +/- 8.2 hours. The concentrations of amiodarone in the tissues were halved within 26.8, 34.9 and 37.45 hours in the heart, lung and fat, respectively. The average concentrations of amiodarone in plasma, heart, lung and fat after single dose were 1.24 micrograms/ml, 1.73 micrograms/mg, 7.61 micrograms/mg and 29.01 micrograms/mg, respectively. The concentration of amiodarone after multiple dosing were halved within 8.4, 5.5, 6.4 and 9.8 days, for the plasma, heart, lung and fat, respectively. The average concentrations of amiodarone in plasma, heart, lung and fat during multiple doses were 0.97 microgram/mg, 7.63 micrograms/mg and 65.01 micrograms/mg respectively. In conclusion, after multiple dosing, the elimination half-life of amiodarone and its fat contents were 3.7 and 2.8 times greater than that after single dosing. The excessive amount of amiodarone observed in fat tissues after multiple dosing is probably the reason for the prolonged elimination half-life. Based on the elimination half-lives data, the time to steady state is about two weeks and the drug should be withheld for less than a mont if a patient required discontinuation because of serious adverse effects.     

Disposition of amiodarone in rats after single and multiple intraperitoneal doses.

The pharmacokinetics of amiodarone was studied after single and multiple dosing in two groups of male Wistar and Albino rats. The first group (40 rats) received a single intraperitoneal (i.p.) dose of amiodarone (100 mg/kg) and 4 rats sacrificed 1, 2, 4, 6, 12, 18, 24, 36, 48 and 72 hours post dosing. The second group (42 rats) received amiodarone (50 mg/kg, i.p. daily) for 5 days a week for 5 weeks and 6 rats were sacrificed at 1, 2, 3, 4, 5, 6 and 8 weeks. Rats of both groups were sampled for blood, heart, lung and fat and the concentrations of amiodarone in these samples were determined using High Performance Liquid Chromatography (HPLC). The elimination of amiodarone from plasma after single dose followed a biphasic pattern with a terminal half-life of 54.7+/-8.2 hours. The concentrations of amiodarone in the tissues were halved within 26.8, 34.9 and 37.45 hours in the heart, lung and fat, respectively. The average concentrations of amiodarone in plasma, heart, lung and fat after single dose were 1.24 microg/ml, 1.73 microg/mg and 29.01 microg/mg, respectivelly. The concentrations of amiodarone after multiple dosing were halved within 8.4, 5.5, 6.4 and 9.8 days, for the plasma, heart, lung and fat, respectively. The average concentrations of amiodarone in plasma, heart, lung and fat during multiple doses were 0.97 microg/ml, 1.41 microg/mg, 7.63 microg/mg and 65.01 microg/mg respectively. In conclusion, after multiple dosing, the elimination half-life of amiodarone and its fat contents were 3.7 and 2.8 times greater than that after single dosing. The excessive amount of amiodarone observed in fat tissues after multiple dosing is probably the reason for the prolonged elimination half-life. Based on the elimination half-lives data, the time to steady state is about two weeks and the drug should be withheld for less than a month if a patient required discontinuation because of serious adverse effects.     

Pharmacokinetic evaluation and safety profile of a 15-minute versus 30-second infusion of palonosetron in healthy subjects

Palonosetron is a potent, selective 5-HT(3) receptor antagonist effective in the prevention of acute and delayed chemotherapy-induced nausea and vomiting. In practice, 5-HT(3) receptor antagonists, including palonosetron, are often coadministered with dexamethasone over approximately 15 minutes, although the approval of palonosetron was based on administration as a 30-second infusion. This open-label, randomized, 2-way crossover trial compared the pharmacokinetics and safety of palonosetron 0.25 mg administered as a 15-minute 50-mL intravenous infusion with a 30-second 5-mL infusion. Aside from an anticipated 40% decrease in maximum plasma concentration after a 15-minute infusion, the pharmacokinetics of palonosetron (including area under the plasma concentration-time curve [AUC], plasma elimination half-life, total body clearance, and apparent volume of distribution at steady state) were similar for both treatments. Both treatments were well tolerated, with no significant changes in vital signs or electrocardiograms. Palonosetron infused over 15 minutes is well tolerated, with an AUC(0-infinity) equivalent to a 30-second infusion.     

Pharmacokinetic and safety evaluation of palonosetron, a 5-hydroxytryptamine-3 receptor antagonist, in U.S. and Japanese healthy subjects

Palonosetron (Aloxi, Onicit) is a selective 5-HT(3) receptor antagonist recently approved by the Food and Drug Administration for the prevention of acute and delayed chemotherapy-induced nausea and vomiting. This study was performed to determine the pharmacokinetics and assess the safety and tolerability of intravenous (IV) palonosetron in healthy U.S. and Japanese subjects. Subjects were administered a single IV dose of palonosetron, ranging from 0.3 to 90 microg/kg in either of two randomized, double-blind, placebo-controlled, ascending-dose studies (n = 80 and n = 32, respectively). Serial blood samples were obtained in both studies to evaluate the pharmacokinetics of palonosetron and its N-oxide metabolite, M9. Intravenous palonosetron was well tolerated across a wide range of doses in both studies. The incidence and severity of adverse events (AEs) were similar between subjects receiving palonosetron and those receiving placebo, with no dose-dependent incidences. The most frequently reported AEs were headache, transient elevation of liver enzymes, and constipation. Systemic exposure (AUC and C(max)) for palonosetron generally increased with increasing dose. Mean total body clearance, elimination half-life, and apparent volume of distribution ranged from 1.11 to 3.90 mL/min/kg, 33.7 to 54.1 hours, and 3.85 to 12.6 L/kg, respectively, in U.S. subjects and from 2.58 to 3.50 mL/min/kg, 30.8 to 36.8 hours, and 6.96 to 9.85 L/kg, respectively, in Japanese subjects. The pharmacokinetics of palonosetron appeared to be independent of dose, with no dose adjustment required in Japanese subjects. The plasma concentration profile of palonosetron, as represented by a half-life of approximately 40 hours, may provide a clinical advantage over other 5-HT(3) antagonists.     

Clonazepam pharmacokinetics: comparison of subcutaneous microsphere injection with multiple-dose oral administration

Nine healthy volunteers participated in a 3-phase clinical pharmacokinetic study of the benzodiazepine derivative clonazepam. During phases I and II, subjects received the conventional oral dosage form of clonazepam, 0.5 mg 3 times daily, for 7 days. Multiple plasma samples were drawn on day 1 and day 7 of the trial and once daily during the washout period after the final dose. Based on nonlinear regression, mean kinetic variables for clonazepam were: absorption half-life, 24 minutes; elimination half-life, 40 hours; apparent oral clearance, 72 mL/min. The extent of accumulation at steady state relative to the first day of treatment averaged 3.3-fold, and was consistent with values predicted based on the elimination half-life. This finding suggests that once-daily dosage with clonazepam would be appropriate for many patients. In phase III of the study, subjects received a single 2.7 mg subcutaneous injection of a microsphere formulation of clonazepam, designed to produce a sustained-release profile. The maximum average plasma clonazepam concentration was 3.0 ng/mL, reached at 72 hours after dosage. Thereafter, plasma concentrations fell slowly over the 13-day sampling period, remaining above 1 ng/mL for 12 days. Overall systemic availability of clonazepam from the microsphere injection, relative to the conventional oral dosage form, was 1.05. Thus, the microsphere preparation of injectable clonazepam provides complete absorption from the injection site, with the intended slow-release pharmacokinetic profile.     

Absorption, distribution, metabolism, and excretion of [1-¹⁴C]-perfluorohexanoate ([¹⁴C]-PFHx) in rats and mice

The absorption, tissue distribution, elimination, and metabolism of [1-¹⁴C]-PFHx in rats and mice dosed orally at 2 or 100 mg/kg was evaluated following a single dose or after 14 consecutive doses. Absorption was rapid in rats as evidenced by a short time to maximum concentration (C_max) of 30 min in male rats and 15 min in female rats at both the 2 and 100 mg/kg dose level. The plasma elimination half-life was somewhat longer in males (1.5-1.7 h) than in females (0.5-0.7 h). Absorption in the mouse was also rapid with the maximum plasma concentration occurring between 15 and 30 min after dosing. The maximum concentration was not appreciably different between male and female mice (8 μg equiv./g at 2 mg/kg; ∼350 μg equiv./g at 100 mg/kg). The primary route of elimination was via the urine. PFHx was not metabolized in rat or mouse hepatocytes, nor were any metabolites observed after oral dosing in either rodent species. Essentially 100% of the dose was eliminated in urine within 24 h demonstrating that PFHx is readily absorbed and bioavailability approaches 100%, even at a dose as high as 100 mg/kg. The route and extent of elimination was unchanged after 14 days of daily dosing. Tissues were collected at three time points (rat: 0.5, 2, and 24 h; mice: 0.25, 1, and 24 h) after dosing to investigate the tissue clearance kinetics of PFHx following a single dose at 2 or 100 mg/kg. In all tissues except skin, PFHx was not quantifiable 24 h after dosing in both sexes of the two species.     

Pharmacodynamics of triazolam after intravenous administration

Triazolam pharmacokinetics and effects on sedation, short-term amnesia, and psychomotor performance were evaluated in 25 normal volunteers as part of a safety and tolerance study of intravenous dosing of triazolam. Triazolam kinetics were linear after intravenous administration of doses up to 1.0 mg with no differences among doses in elimination half-life, volume of distribution, or clearance. The hepatic extraction ratio ranged from 0.14 to 0.37, suggesting that triazolam should undergo moderate first-pass metabolism after oral administration. The duration and extent of sedation, decrement in psychomotor performance test scores, and amnesia were dose related, but all subjects returned to baseline alertness and function within eight hours of dosing. The time-course of effects on memory and psychomotor performance were related to triazolam plasma concentration profile using an Emax model for effect and a two-compartment pharmacokinetic model. The probability of a subject being asleep was related to triazolam plasma concentrations using logistic regression. These models indicate that intravenous doses of 0.25 to 0.5 mg triazolam would be effective for use preoperatively for short surgical procedures.     

Clinical evaluation of ceftazidime in infections in neonates and premature infants

Ceftazidime (CAZ) was evaluated in the treatment of infections in neonates and premature infants. In 1 mature neonate (age: 14 days) administered with 30.3 mg/kg of CAZ by a single bolus intravenous injection, the serum concentration of CAZ was 50 micrograms/ml at 30 minutes after the dosing, and the elimination half-life was 1.38 hours. The urinary recovery rate of administered CAZ during the first 6 hours was 52.9%. In 6 neonates (mean gestational period: 37.8 weeks, mean birth weight: 2,508 g, mean age: 3.7 days) administered with ca. 20 mg/kg of CAZ by single bolus intravenous injections, the mean serum concentration of CAZ was 63.6 micrograms/ml at 30 minutes after the dosing, and the half-life was 3.78 hours. In 3 out of the above 6 neonates, the mean urinary recovery rate of CAZ during the first 6 hours was 59.8%. Five neonates and 2 infants with infections were given 18.4-65.9 mg/kg of CAZ b.i.d.-q.i.d. by intravenous injections. One of these cases was excluded from an evaluation for clinical efficacy, because CAZ was given only for 2 days. In the remaining 6 cases, clinical efficacy was excellent in 1 case of urinary tract infection (E. coli + E. faecalis), good in 3 cases of pneumonia (P. aeruginosa + K. pneumoniae: 1, P. aeruginosa: 1, and causative organism unknown: 1), and poor in 1 case of sepsis (S. aureus). In 1 case of asphyxia neonatorum contaminated with meconium, CAZ was used prophylactically, resulting with no infection. No clinically adverse effect was observed. Also no abnormality was observed in laboratory analyses in the 6 cases.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics, metabolism and excretion of intravenous [l4C]-palonosetron in healthy human volunteers

Palonosetron (Aloxi(R), Onicit(R)) is a potent, single stereoisomeric 5-HT(3) receptor antagonist developed to prevent chemotherapy-induced nausea and vomiting. The pharmacokinetics and metabolic disposition of a single intravenous [(14)C]-palonosetron (10 microg/kg, 0.8 microCi/kg) bolus dose were evaluated in six healthy volunteers (three males, three females) using serial blood, plasma, urine and fecal samples obtained over 10 days. The safety, tolerability and cardiac effects were assessed. Radiolabeled metabolic characterization revealed that unchanged palonosetron accounted for 71.9% of the total radioactivity in plasma over 96 h, with an extensive distribution volume (8.34 l/kg) and mean plasma elimination half-life of 37 h. Approximately 83% of the dose was recovered in urine ( approximately 40% as unchanged drug, with 50% metabolized; M9 and M4 were the major metabolites) and 3.4% in feces. Hydrolysis of urine samples suggests that the metabolites are not beta-glucuronide or sulfate conjugates of the parent drug or metabolites. The blood to plasma concentration ratio of the total radioactivity was 1.2, on average, indicating little selective partitioning in erythrocytes. Palonosetron was generally well tolerated; headache was the most frequently reported adverse event. Electrocardiograms and 72 h Holter monitoring revealed no clinically significant changes. Palonosetron circulates in plasma mainly as the parent drug. Renal elimination is the primary excretion route, with parent drug and metabolites M9 and M4 accounting for the majority of palonosetron disposition. These results indicate that both renal and hepatic routes are involved in the elimination of palonosetron from the body.     

The human pharmacokinetics of cefotaxime and its metabolites and the role of renal tubular secretion on their elimination

The pharmacokinetics of cefotaxime were investigated in human volunteers given constant intravenous infusions, intravenous bolus, and intramuscular doses of the drug. After intravenous dosing, the plasma levels of cefotaxime declined in a biphasic manner with a terminal half-life varying between 0.92 and 1.65 hr. Moreover, the pharmacokinetics were linear up to at least a 2.0 g dose for volume of distribution based on area (23.3-31.3 l), plasma clearance (249-2.88 ml/min), and renal clearance (151-177 ml/min). Renal tubular secretion of intact cefotaxime and each of its metabolites was demonstrated by its interaction with probenecid, although the ratio of drug to metabolites ultimately excreted in urine after probenecid was similar to that seen normally (54 +/- 6, 19 +/- 4, 6.5 +/- 0.7 and 5.5 +/- 0.7% for cefotaxime, DACM, M2, and M3, respectively, when calculated as a percentage of the dose). The observed half-lives of DACM, M2, and M3 were 2.3 +/- 0.4, 2.2 +/- 0.1 and 2.2 hr, respectively. However, when the true half-life of DACM was calculated (0.83 +/- 0.23 hr) it was not only significantly shorter than that observed but also shorter than that for intact cefotaxime. The plasma clearance of DACM (744 +/- 226 ml/min) was much higher than that of cefotaxime while the volume of distribution was of a similar order (56 +/- 24 l). When administered intramuscularly, there was good absorption of cefotaxime from the site of injection (92-94%) giving maximum plasma levels of the drug of between 30 and 35 mg/l at approximately 40 min after dosing. Thereafter, the plasma levels of cefotaxime declined in a monophasic manner with a half-life (1.0-1.2 hr) similar to that of the terminal half-life seen after intravenous administration. Lidocaine had no significant effect on either its absorption or elimination kinetics.     

Pharmacokinetics of CS-866, a new angiotensin II receptor blocker, in healthy subjects

CS-866, a novel angiotensin II receptor blocker, is rapidly and completely metabolized to RNH-6270, its active metabolite. The pharmacokinetics of RNH-6270 following oral CS-866 or intravenous RNH-6270 administration was determined in 104 healthy male volunteers. The pharmacokinetics of RNH-6270 was linear over dose ranges of 1 to 32 mg (intravenous RNH-6270 administration) and 10 to 160 mg (oral CS-866 administration). The time to maximum plasma concentration of RNH-6270 after oral CS-866 administration ranged from 1.4 to 2.8 hours, and the terminal elimination half-life ranged from 12 to 18 hours. Absolute bioavailability of RNH-6270 after oral administration of CS-866 was 26%. Administration of CS-866 once daily for 10 days did not result in drug accumulation. When administered intravenously, RNH-6270 has a volume of distribution of 15 to 25 L. Approximately 35% to 50% of RNH-6270 is excreted unchanged in the urine. CS-866 was safe and well tolerated at doses of up to 160 mg/day.     

Variability of oral bioavailability for low dose methotrexate in rats.

The effects of food, antibiotics, diclofenac sodium (DS) and methotrexate (MTX) on oral bioavailability (BA) of MTX were examined in rats. Feeding didn't vary the plasma concentrations after intravenous dosing of 0.5 mg/kg MTX, but enhanced those after oral dosing, and the oral BA. The twice daily oral doses of 40 mg/kg neomycin sulfate (NS) or mixed antibiotics (200 mg/kg NS + 200 mg/kg streptomycin sulfate + 200 mg/kg bacitracin) for 5 days didn't influence the plasma concentrations after intravenous dosing of 0.5 mg/kg MTX, but induced the decreased Cmax and the delayed MRT after oral dosing. The plasma concentrations after intravenous or oral dosing of 2.5 mg/kg MTX in rats orally dosed with 1 or 5 mg/kg/day DS for 4 days were similar to those in the control rats, while the pre-treatment of 25 mg/kg/day DS delayed the elimination of MTX but didn't change the oral BA. The plasma concentrations after intravenous or oral dosing of 2.5 mg/kg MTX in rats, which received the intermittent oral doses of 7.5 mg/kg/3 doses/week MTX for 4 weeks, were comparable to those in the control rats, but the daily pre-treatment of 0.2 mg/kg/day MTX for 4 weeks increased the plasma concentrations after oral dosing, and the BA.     

Flunitrazepam and lormetazepam do not affect the pharmacokinetics of the benzodiazepine antagonist Ro 15-1788.

Following a single intravenous dose of 0.1 mg/kg, the pharmacokinetics of Ro 15-1788, a specific benzodiazepine antagonist, have been investigated in 20 healthy male volunteers. In random order injection of Ro 15-1788 has been preceded (5 min) by intravenous dosing with 0.06 mg/kg of lormetazepam (n = 6), 0.03 mg/kg of flunitrazepam (n = 8) or placebo (n = 6). The rapid elimination of the antagonist could be characterized by an elimination half-life between 0.9 to 1.4 h and a total plasma clearance of 727 to 1440 ml/min. These single dose studies indicate that the disposition of Ro 15-1788 was not affected by the acute coadministration of both benzodiazepines.     

Flecainide: single and multiple oral dose kinetics, absolute bioavailability and effect of food and antacid in man.

The kinetics of flecainide after single intravenous (2 mg kg-1) and oral (200 mg) dosing, absolute bioavailability, effects of food and aluminium hydroxide on flecainide absorption and steady-state kinetics following twice daily oral dosing (200 mg) have been evaluated in ten healthy subjects. Absolute bioavailability of oral flecainide averaged 70% (range 60-86%). Rate and extent of flecainide absorption were not significantly affected by food nor by concomitantly administered aluminium hydroxide. The apparent volume of distribution of 5.5 +/- 0.3 l kg-1 indicates wide distribution of flecainide in tissues. Estimated elimination half-lives from plasma data averaged 9.3 to 12.4 h (single oral dose studies), 11.8 h (single i.v. dose), and 11.5 h (multiple oral dose). Half-lives calculated from urinary excretion data corresponded well with those calculated from plasma data. Flecainide elimination takes place both by nonrenal (metabolic) clearance and renal excretion of the intact drug involving glomerular filtration and active tubular secretion. Following i.v. dosing CLNR and CLR averaged respectively 3.24 +/- 0.80 and 2.38 +/- 0.49 ml min-1 kg-1. After 200 mg twice daily oral treatment steady state was reached within 3-4 days with trough and peak plasma levels on day 8 of 457 and 662 ng ml-1, which are well within the therapeutic range.