Felbamate pharmacokinetics in the rat, rabbit, and dog.

Rats, rabbits, and dogs were given single iv or single and multiple oral doses of felbamate ranging from 1.6-1000 mg/kg. Absorption of oral drug was complete in all species. The mean Cmax increased with dose from 13.9 to 185.9 micrograms/ml in rats, from 19.1 to 161.9 micrograms/ml in rabbits, and from 12.6 to 168.4 micrograms/ml in dogs. The tmax also increased with dose from 1-8 hr in rats, 8-24 hr in rabbits, and 3-7 hr in dogs. The plasma elimination half-life for the drug increased with dose from 2-16.7 hr in rats, 7.2-17.8 hr in rabbits, and 4.1-4.5 hr in dogs. A proportional increase in Cmax with dose was observed in all species up to 300-400 mg/kg doses. A biexponential equation fitted the drug plasma concentration vs. time data well. For multiple oral doses of 50 mg/kg or less, projected and observed steady-state concentrations agreed well. Animals dosed with [14C]felbamate eliminated most of the radioactivity in urine (58-87.7%), less in feces (7-23.7%), with considerable amounts in the bile. In rats, radioactivity was readily distributed into tissues and crossed the placenta and blood-brain barrier, but no accumulation in any tissue was observed. The volume of distribution was 131, 54, and 72% of body weight for rats, rabbits, and dogs, respectively. Binding of drug to rat, rabbit, and dog plasma proteins ranged from 22.4-35.9%. The overall plasma clearance of the drug for rats, rabbits, and dogs was 327, 52, and 108 ml.h-1.kg-1, respectively. Renal clearance of unchanged drug accounted for an estimated 20-35% and hepatic clearance due to metabolism for 65-80% of the overall clearance.     

Species differences in the pharmacokinetics of recainam, a new anti-arrhythmic drug

The pharmacokinetics of recainam, an anti-arrhythmic drug, were compared in mice, rats, rabbits, dogs, rhesus monkeys, and man. Bioavailability was virtually complete in monkeys and dogs, 67 per cent in man and 51 per cent in rats. Non-linear kinetics between the oral and i.v. dose in rabbits precluded estimation of bioavailability. Linear plasma dose proportionality occurred in dogs between 6 and 60 mg kg-1 oral doses and rhesus monkeys between 1 and 15 mg kg-1 i.v. doses. A greater than proportional increase in the plasma AUC of recainam occurred between oral doses ranging from 54-208 mg kg-1 in mice, 25-110 mg kg-1 in rats, and 50-100 mg kg-1 in rabbits. In human subjects, the AUC/unit dose was linear between 400 and 800 mg. The terminal elimination t1/2 of recainam ranged from 1-5h in laboratory animals and man. The plasma Cmax and AUC of recainam were virtually identical after single or multiple (21 day) oral doses in dogs. After an i.v. dose, plasma clearance of recainam (l kg-1 .h) was 4.9-5.2 in rats and rabbits and 0.4-1.9 in dogs, rhesus monkeys, and man. The steady state volume of distribution was 2-5 times larger than the total body water of laboratory animals and man. Recainam was very poorly bound (10-45 per cent) to the serum proteins of rodents, rabbits, dogs, rhesus monkeys and man. In rhesus monkeys and man, recainam accounted for 10 per cent and 70 per cent, respectively, of the plasma radioactivity at 6 h post-dose. The pharmacokinetic profile of recainam in dogs most closely resembled that of man.     

Stereoselectivity in the metabolism of disopyramide enantiomers in rat and dog

The metabolism and pharmacokinetics of (S)-(+)- and (R)-(-)-disopyramide (DP) were compared in laboratory animals. In rats, after oral administration of (S)-(+)-DP phosphate salt at a dose of 38.8 mg of DP free base per kg, the mean maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were 1.43 micrograms/ml and 4.47 micrograms . hr/ml, respectively, and after (R)-(-)-DP administration, the values were 4.93 micrograms/ml and 17.05 micrograms . hr/ml, respectively. Similar recoveries (approximately 55% of the dose) of DP and its metabolites in the urine and bile of rats were obtained after administration of the individual (S)-(+)- and (R)-(-)-enantiomers of DP. These results indicate similar oral absorption of the two enantiomers, but greater metabolism with (S)-(+)-DP in rats. In dogs, the AUC of DP after iv administration of (R)-(-)-DP phosphate salt at a dose of 15 mg of DP free base per kg was 1.6 times greater than that after (S)-(+)-DP phosphate salt. Inasmuch as volumes of distribution of the two enantiomers were similar, this difference can be attributed to a difference in the elimination rates of the enantiomers. After an oral dose, the difference in AUC of the two enantiomers was greater than that after an iv dose. The mean values of Cmax and AUC after a 15-mg/kg oral dose of (S)-(+)-DP were 1.32 micrograms/ml and 4.07 micrograms . hr/ml, respectively, and with (R)-(-)-DP the values were 2.88 micrograms/ml and 9.21 micrograms . hr/ml, respectively. The Cmax and AUC of the total drug-related materials (drug plus its metabolites) were similar. These results, together with the similarity in the urinary excretion of total drug related compounds, indicated that after equivalent doses of the two enantiomers, oral absorptions were similar, but the first-pass metabolism was greater with (S)-(+)-DP. The present study also demonstrated that N-dealkylation in dogs and arylhydroxylation in rats are stereoselective metabolic pathways, thus illustrating species differences in the stereoselective metabolism of DP.     

Effects of nicorandil and verapamil, antianginal agents, on plasma digoxin concentrations in rats and dogs

The effects of equihypotensive doses of nicorandil and verapamil on plasma digoxin concentrations have been assessed in rats and dogs. In a single digoxin dose study, digoxin (1 mg kg-1) alone, or in combination with nicorandil (5 mg kg-1) or verapamil (25 mg kg-1) was given orally to rats. When given chronically to rats, a single dose of digoxin (1 mg kg-1) orally for 7 consecutive days was followed, on day 8, by digoxin alone, or together with nicorandil (5 mg kg-1) or verapamil (25 mg kg-1). In dogs, a loading dose of digoxin (50 micrograms kg-1) was given orally on day 1, then 25 micrograms kg-1 was administered for the following 6 days. On day 8, digoxin (50 micrograms kg-1) was given with nicorandil (5 mg kg-1) or verapamil (20 mg kg-1). In rats, the AUC0-24 and Cmax of plasma digoxin were enhanced significantly by coadministration of verapamil, but not by nicorandil. In dogs, verapamil significantly increased the Cmax of plasma digoxin, but not the AUC. Nicorandil had no effect on either parameter.     

Pharmacokinetic profile and bioavailability of a new pharmaceutical formulation of isosorbide-5-mononitrate sustained-release formulation

The pharmacokinetic profile and the bioavailability of a new galenic formulation of isosorbide-5-mononitrate sustained released capsules (Olicard 40 retard) was tested under standardized conditions. 12 healthy, male volunteers (mean age 24.9 +/- 3.0 years) in a randomized, intraindividual crossover design (wash-out phase: 6 days) received the isosorbide-5-mononitrate sustained-release capsules (testformulation) and a standard-release formulation of the same active substance as single dose (40 mg each). Venous blood sampling for analysing the plasma concentration of isosorbide-5-mononitrate was done before and at 21 fixed times after medication. The AUC0----36h of the concentration/time curve was calculated using the linear trapezoidal rule and the AUC0----infinity extrapolated after computing the half-life of the terminal elimination phase. The leading variable was the AUC0----infinity. For the sustained-release preparation an AUC0----36h of 5764.5 +/- 909 ng/ml.h was measured, an AUC0----infinity of 5863.9 +/- 981.9 ng/ml.h was calculated, with a peak maximum (Cmax) of 472.5 +/- 29.7 ng/ml after 2.9 +/- 0.5 h (tmax). For the standard-release formulation an AUC0----36h of 5679.8 +/- 690.3 ng/ml.h was measured, an AUC0----infinity of 5688.7 +/- 695.7 ng/ml.h was calculated, with a peak maximum (Cmax) of 842.4 +/- 100.2 ng/ml after 1.2 +/- 0.2 h (tmax). The bioavailability of the standard-release formulation was postulated to be 100%. The non-parametric calculation of the bioavailability-ratio (geometric Walsh-averages) was 101.47% (95% confidence limits 85.24% to 121.09%). There was no statistically significant difference between the both galenical formulations, the sustained-release preparation has no influence on the total amount of resorption.(ABSTRACT TRUNCATED AT 250 WORDS)     

Tolerance-dependence and serum elimination of morphine in rats implanted with morphine pellets.

1. In order to determine whether the degree of tolerance to and physical dependence on morphine induced by pellet implantation procedure in the rat depends on the dose used and the kinetic parameters, the effect of implantation of different number of pellets on tolerance-dependence and elimination kinetics of morphine from serum was determined. 2. Male Sprague-Dawley rats were implanted subcutaneously with pellets. Each pellet contained 75 mg of morphine free base. Three schedules of implantation were used. They included 2 pellets during a 3-day period (2/3), 4 pellets during a 3-day period (4/3) and 6 pellets during a 7-day period (6/7). Placebo pellets which did not contain morphine were implanted in rats which served as controls. 3. The degree of tolerance to and physical dependence on morphine increased as the number of morphine pellets implanted increased. 4. In separate groups of rats implanted with pellets, elimination kinetics of morphine was studied using radioimmunoassay. The kinetic parameters were: area under serum morphine concentration time curve (AUC0----infinity), serum concentration of morphine extrapolated to time zero (Cmax), half-life (t1/2), elimination rate constant (k), mean residence time (MRT) and total body clearance (Clt). 5. The AUC0----infinity and Cmax increased in proportion to the number of pellets implanted. The t1/2, k, MRT and Clt values for 2/3 and 4/3 schedules did not differ, but for 6/7 schedule were significantly different from the other two schedules. The degree of tolerance to and physical dependence on morphine was directly related to the AUC0----infinity and Cmax. The longer t1/2 and MRT and lower Clt and k values in 6/7 schedule may reflect a saturation of glucuronic acid transferase, the main enzyme metabolizing morphine in the liver, and may account for the greater degree of tolerance and physical dependence.     

Toxicological studies on pipemidic acid. V. Effect on diarthrodial joints of experimental animals.

Pipemidic acid (PPA) orally given in a dose of 100 mg/kg/day or more was found to cause lame gait in immature beagle dogs of about 3 months old. Their diarthrodial joints were abnormal with increased synovial fluid and blister formation under the outer layer of the articular cartilage. However, such an abnormality was not found in dogs younger than 2 weeks or older than 12 months. The blisters were formed at the joint areas bearing the body weight at a time when PPA was considered to be present there. Nalidixic and piromidic acids, structural analogues of PPA, also caused abnormality similar to PPA. The severity of the arthropathy was slight with piromidic acid as compared with PPA and nalidixic acid. The gait abnormality was almost disappeared spontaneously even if medication was continued. The incidence of the arthropathy was not or rarely observed in any young rats, rabbits and monkeys.     

Linearity of the pharmacokinetics of phosphomycin in serum and interstitial tissue fluid in rabbits

A study was carried out on the access and residence of (-)(1R,2S)-1,2-epoxypropylphosphonic acid (phosphomycin) in interstitial tissue fluid produced experimentally by subcutaneous implantation of spiral steel cages after administration of doses of 20, 30 and 60 mg/kg of the antibiotic to rabbits. The levels reached by the drug in serum and interstitial tissue fluid (ITF) were determined by a microbiological plate diffusion method. The elimination half-lives of phosphomycin ranged between 1.16 and 1.57 h. These values are similar to those found for the disappearance half-lives from ITF. Phosphomycin reached maximum concentrations in ITF between 31.95 and 80.37 micrograms/ml. Linear relationships were established between the (AUC) 0 infinity in serum, the (AUC) 0 infinity in ITF and Cmax in ITF and the doses studied, revealing the non-dose-dependent kinetics of phosphomycin. The linearity of phosphomycin kinetics was checked in serum and ITF by applying the superposition principle.     

Transfer of cefotetan into exudates from excoriated skin wounds

Transfer of cefotetan (CTT) into exudates from excoriated skin wounds was studied in 9 adult patients. Each subject was given an intravenous bolus injection of 50 mg/kg of body weight. Concentrations of CTT in serum and in exudate fluid were determined by bioassay using Escherichia coli NIHJ as the test organism. The mean (+/- S.D.) CTT concentration in serum reached 274.3 +/- 78.3 micrograms/ml at 30 minutes after the injection and decreased to 30.0 +/- 12.0 micrograms/ml at 8 hours after the injection. The peak value of CTT in exudate fluid was 143.1 +/- 22.3 micrograms/ml at 1 hour. Eight hours after the injection, the mean concentration in the exudate was 25.7 +/- 21.1 micrograms/ml. The data obtained were analysed pharmacokinetically: CTT concentrations in serum were analysed by two-compartment model, and those in exudate fluid from excoriated skin wounds were analysed by the model in which skin was considered as a small part of the peripheral compartment. Thus T1/2(beta) of CTT levels in serum was calculated as 2.38 hours, AUC0----infinity was 1,000.2 micrograms X hr/ml and Vd was 164.5 ml/kg. Tmax and Cmax of CTT levels in exudates were calculated as 1.05 hours and 131.2 micrograms/ml, respectively.     

Pharmacokinetics of triflusal and its main metabolite in rats and dogs.

The methods for determining plasma concentrations of triflusal (2-acetoxy-4-trifluoromethyl benzoic acid) that have been described, do not distinguish between the drug and its main metabolite HTB (2-hydroxy-4-trifluoromethyl benzoic acid). In the present study, we have developed a new analytical technique based on HPLC that enabled us to carry out a pharmacokinetic study of the drug and its metabolite in animals. An intravenous or oral dose of 50 mg/kg was administered to male Sprague-Dawley rats, and 15 mg/kg was administered to beagle dogs. Plasma levels of triflusal and HTB were determined. In rats, triflusal was quickly eliminated from plasma with a biological half-life (t1/2) of 2.7 min and a clearance (Cl) of 73.4 (ml/kg)/min. The elimination of HTB was much slower with a t1/2 of 21.5 h and a Cl of 5.1 (mg/kg)/h. The maximum concentration (Cmax) of triflusal in rats after an oral administration was 8.1 +/- 2.0 micrograms/ml reached between 2.5 and 10 min. The Cmax of HTB was 237.7 micrograms/ml and was achieved at 0.7 h. The bioavailability of triflusal in rats was only 10.6% while the bioavailability of HTB was more than 100% indicating an important first pass effect. In dogs the t1/2 of triflusal was 14.4 +/- 5.9 min and the Cl was 25.1 +/- 4.7 (ml/kg)/min. HTB was also eliminated very slowly with a t1/2 of 71.1 +/- 12.5 h and a Cl of 2.4 +/- 0.3 (ml/kg)/h. The Cmax of triflusal in dogs was 13.3 +/- 2.9 micrograms/ml and was reached after 19.2 +/- 6.1 min (tmax).(ABSTRACT TRUNCATED AT 250 WORDS)     

Studies on the absorption and excretion of rokitamycin in infant beagle dogs. Comparison with adult beagle dogs

Absorption and excretion of rokitamycin (RKM) were studied after oral administration of 50 mg/kg to fasted infant and adult Beagle dogs. In infant Beagle dogs, the mean plasma level of RKM reached its peak of 6.53 micrograms/ml in 15 minutes after administration. The area under the curve (AUC) value was 11.04 micrograms.hr/ml. In adult Beagle dogs, the mean plasma level of RKM reached its peak of 8.62 micrograms/ml in 30 minutes after administration. The AUC value was 18.25 micrograms.hr/ml. Ratios of Cmax and AUC value in infant Beagle dogs to those in adults were about 75% and 60%, respectively. In infant Beagle dogs, urinary excretion of RKM was 2.55% of the dose within 24 hours. In adult Beagle dogs, urinary excretion of RKM was 3.03% of the dose within the same period. The excretion ratio of RKM in infant Beagle dogs was about 85% of the adults' value.     

Absolute bioavailability of moxonidine

In a randomized 2-way cross-over study with eighteen healthy male volunteers, two moxonidine preparations (tablets, treatment A vs. intravenous solution, treatment B) were tested to investigate absolute bioavailability and pharmacokinetics of moxonidine. The preparations were administered as single doses of 0.2 mg; prior to and up to 24 h after administration blood samples were collected and the plasma moxonidine concentrations determined. Urine samples were collected prior to and at scheduled intervals up to 24 h after administration for the determination of unchanged moxonidine. Moxonidine plasma and urine concentrations were determined by a validated gas chromatographic/mass spectrometric method with negative ion chemical ionization. The mean areas under the plasma concentration/time curves were calculated as [mean +/- standard deviation] 3438 +/- 962 pg.h/ml (AUC(0----Tlast)) and 3674 +/- 1009 pg.h/ml (AUC(0----infinity)) for treatment A; 3855 +/- 1157 pg.h/ml (AUC(0----Tlast)) and 4198 +/- 1205 pg.h/ml (AUC(0----infinity)) for treatment B. Mean peak plasma concentrations of 1495 +/- 646 pg/ml were attained at 0.56 +/- 0.28 h after oral treatment, mean peak plasma concentrations after intravenous treatment reached 3965 +/- 1342 pg/ml at 0.17 +/- 0.01 h (= coinciding with end of infusion). The mean terminal half-lives of moxonidine were derived as 1.98 h after administration of the tablet and as 2.18 h after infusion. The amounts of moxonidine excreted in urine during the 24 h following administration (Ae(24h)) in absolute figures and as percentage of the dose administered were 102 +/- 26 micrograms or 51 +/- 13% for the tablet and 122 +/- 33 micrograms or 61 +/- 16% for the infusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relative bioavailability of three cefixime formulations

Three galenic formulations of cefixime (tablet, syrup and dry suspension) containing 200 mg each were compared with respect to their relative bioavailability in twelve healthy volunteers. All three formulations showed reliable absorption. Mean peak plasma concentrations were reached after 3.3-3.5 h, mean terminal half lives were 2.9-3.1 h. 18-24% of the dose administered were recovered unchanged in the urine. Best bioavailability was obtained with the dry suspension (AUC0-infinity = 25.8 +/- 7.0 micrograms/ml h; Cmax = 3.4 +/- 0.9 microgram/ml), followed by the tablet (AUC0-infinity = 20.9 +/- 8.1 micrograms/ml h; Cmax = 3.0 +/- 1.0 micrograms/ml) and the syrup which is based on triglycerides (AUC0-infinity = 17.8 +/- 5.9 micrograms/ml h; Cmax = 2.4 +/- 0.7 micrograms/ml). The statistical analysis resulted in bioinequivalence between dry suspension and syrup. It is concluded that best bioavailability of cefixime after oral administration is guaranteed when taken in an "aqueous medium" either as dry suspension or as tablet with "plenty of liquid".     

Plasma tenoxicam concentrations after single and multiple oral doses

The pharmacokinetics of single- and multiple-dose administration of tenoxicam 20 mg were evaluated in 8 healthy males. Maximum plasma concentration (Cmax) after the first dose was 2.76 +/- 0.48 micrograms/ml (mean +/- s.d.) and the time to reach Cmax (Tmax) was 5.0 +/- 3.0 h. The area under the plasma concentration-time curve (AUC0-infinity) after a single administration of tenoxicam was 242.5 +/- 73.5 micrograms x h/ml. The elimination half-life (t1/2) was 66.3 +/- 15.8 h and the plasma concentration at 24 hours after dosing (Cmin) was 1.84 +/- 0.33 micrograms/ml. Steady-state plasma concentrations of tenoxicam were virtually reached after 10 consecutive daily doses. At steady-state, Cmax averaged 13.63 +/- 3.33 micrograms/ml and Tmax remained 5.0 +/- 3.0 hours. AUC within a dosing interval at steady-state was 262.2 +/- 67.0 micrograms x h/ml, Cminss was 9.67 +/- 3.25 micrograms/ml, and t1/2 averaged 74.2 +/- 13.3 h. The average fluctuation during multiple-dose administration was 26.8 +/- 8.0% and the accumulation ratio was 5.82 +/- 0.60. Steady-state pharmacokinetic parameters predicted from the first-dose data slightly underestimated observed values, but the results supported the assumption of linear pharmacokinetics during multiple-dose tenoxicam administration.     

Bioequivalency of oral suspension formulations of cefixime

A study was performed in 24 healthy male subjects to establish that two suspension formulations of cefixime were bioequivalent to each other and to a reference oral solution. A single 400 mg oral dose of the drug was given in a randomized three-way crossover design as two suspensions (a research suspension (RS) used during clinical trials and a suspension intended for marketing (MS] and a reference oral solution (SOL). Each dose was separated from the other by a 3-day washout period. Mean peak serum concentrations (Cmax) were 4.67, 4.10, and 4.27 micrograms ml-1 after the MS, RS, and SOL, respectively. Although comparison (ANOVA) of the mean pharmacokinetic parameters for cefixime found significant differences (p less than 0.05) in Cmax, the time to Cmax, and area under the serum concentration time curve (AUC 0----infinity) values among the three formulations, the mean differences were less than 20 per cent. No significant differences (p greater than 0.05) were found in either the elimination half-life or renal clearance of unchanged drug. Overall, with a 98 per cent power to detect a 20 per cent difference in AUC0----infinity or urinary recovery values between the formulations tested, the results show that the MS was bioequivalent to the RS and that both suspensions were bioequivalent to the SOL.     

The plasma pharmacokinetics of iophenoxic and iopanoic acids in goat.

1. The comparative plasma pharmacokinetics of two organic iodine-containing compounds were evaluated in the goat for their suitability as markers in wildlife studies. 2. After oral administration of a single dose, the plasma elimination half-life for iopanoic acid was considerably more rapid (t1/2 of 1-2 days) than that of iophenoxic acid (t1/2 of 81 days). 3. Similar peak plasma concentrations were obtained after administration of iophenoxic acid (1.5 mg/kg) and iopanoic acid (25 mg/kg); however, the AUC0----infinity for iopanoic acid at doses of 25, 50, and 100 mg/kg were 201 +/- 39, 604 +/- 225, and 1292 +/- 721 (micrograms h/ml +/- SD), respectively, which were less than the value of 36,600 +/- 6387 for the oral administration of iophenoxic acid at 1.5 mg/kg. 4. Iophenoxic acid was chosen as a suitable marker because of its persistence at detectable concentrations in the plasma for 5 months.     

Pharmacokinetics of cefprozil in infant and adult beagle dogs]

The Pharmacokinetics of cefprozil was studied upon oral administration of 25 mg/kg to fasted infant and adult Beagle dogs. When the pharmacokinetic parameters between infant and adult dogs were compared, the mean peak concentration (Cmax) in infant dogs (21.2 micrograms/ml) was significantly (P < 0.01) lower than that of adult dogs (27.8 micrograms/ml). But significant differences were not found in the areas under the concentration-time curve (AUC, in infant dogs: 121 micrograms.hr/ml, in adult dogs: 130 micrograms.hr/ml), half-lives (T 1/2, in infant dogs: 4.7 hours, in adult dogs: 4.7 hours) or urinary recovery rates (UR, in infant dogs: 36.3%, in adult dogs: 34.7%) between the 2 groups. These results suggest the distribution volumes of infant dogs are larger than those of adult dogs, and the absorption rates of infant dogs are slower than those of adult dogs, whereas the absorption quantities are similar.     

Pharmacokinetics of ceftizoxime suppository in experimental animals

Ceftizoxime suppository (CZX-S) was administered rectally to mice, rats and dogs, and the pharmacokinetics were studied in comparison with those after intravenous, intramuscular and subcutaneous administration of ceftizoxime (CZX). Absorption of CZX given rectally was rapid in all animals, similar to intramuscular or subcutaneous administration. The peak serum levels of CZX in mice, rats and dogs when administered rectally at a dose of 25 mg/kg were 23.1 micrograms/ml at 7.5 minutes, 23.5 micrograms/ml at 15 minutes and 25.2 micrograms/ml at 15 minutes, respectively. These values were about 76%, 68% and 42% of the values for subcutaneous or intramuscular administration in mice, rats and dogs at the same respective doses. Urinary recoveries of CZX after rectal administration of 25 mg/kg were 44.2% (0-12 12 hours) in rats and 27.7% (0-6 hours) in dogs, and 2.7% (0-6 hours) of the dose was excreted into bile fluid in rats. Organ distribution of CZX when administered rectally to rats was similar in distribution pattern to that of muscular administration, although its concentrations in various organs were slightly lower than those for intramuscular administration, as was the case for serum concentration. Serum concentrations of CZX were proportionately elevated with dose when dogs were rectally administered CZX-S in doses of 12.5, 25 and 50 mg/kg. In the case of multiple administrations (t.i.d. for 10 days) of CZX-S to dogs, no remarkable difference was found in serum concentrations of CZX in comparison with single doses, and no accumulation of CZX was demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative articular toxicity of garenoxacin,a novel quinolone antimicrobial agent,in juvenile beagle dogs

The articular toxicity of garenoxacin (formerly T-3811 or BMS-284756) was experimentally examined utilizing juvenile beagle dogs. Garenoxacin and two other reference quinolones were administered at intravenous dosages of 30 and 60 mg/kg. Each group consisted of 3 male dogs (Experiment I). Oral dosages of 50 mg/kg of 3 compounds were also given daily to male only and female only groups (Experiment II) over a period of 7 days. We evaluated the articular toxicity of garenoxacin compared to ciprofloxacin and norfloxacin. In Experiment I, no articular toxicity was detected in the 30 mg/kg garenoxacin group. One animal from the 60 mg/kg garenoxacin group developed detectable histopathological lesions in the articular cartilages of the shoulder, elbow and knee joints. In the 30 mg/kg ciprofloxacin group and the 30 and 60 mg/kg norfloxacin groups, histopathological articular cartilage lesions of the shoulder, elbow, carpus, hip, knee and tarsus joints were observed in all of the dogs. The area under the plasma concentration-time curve (AUC0-->infinity) values, after the first dose was administered, for the 30 mg/kg groups given garenoxacin, ciprofloxacin and norfloxacin were 164, 68.1 and 65.7 micrograms.hr/mL, respectively. In Experiment II, the degree of histopathological change was most significant in the ciprofloxacin group, followed by the norfloxacin group, and with comparatively the least changes in the garenoxacin group. The AUC0-->infinity values, obtained after the 6th day of antimicrobial administration, were 202 and 173 micrograms.hr/mL for male and female dogs, respectively, from the 50 mg/kg garenoxacin group. The AUC0-->infinity values for the garenoxacin group after the 6th daily administration were 7.8 to 17.0 times greater for male dogs and 3.8 to 13.2 times greater for female dogs than those obtained from the ciprofloxacin and norfloxacin groups. The concentrations of garenoxacin in the synovia, articular cartilage and the synovialis 4 hr following the last garenoxacin administration were 2.0 to 6.5 times higher for male dogs and 1.5 to 3.3 times higher for female dogs than the antimicrobial levels measured in the ciprofloxacin and norfloxacin groups. As discussed above, although the garenoxacin concentrations in plasma and joint tissue were higher than those for ciprofloxacin and norfloxacin, however, the articular toxicity of garenoxacin was much less than that of the other two antimicrobials.     

Diltiazem pharmacokinetics in elderly volunteers after single and multiple doses

In young healthy volunteers diltiazem does not have linear kinetics between single and multiple doses. Elimination half-life increases and gives AUC's and Cmax higher than those predicted from single dose data. Kinetics of diltiazem were assessed in 16 healthy elderly after a single 60 mg dose and in 24 healthy elderly after 60 mg every 8 h for 7 days. Thirteen participants completed both studies. Elimination half-life, AUC0-24, AUC0-infinity, and Cmax were (mean +/- SE) 7.4 (1.2) h, 349 (34) ng/ml.h, 392 (44) ng/ml.h, and 43 (5) ng/ml respectively after a single dose. After multiple doses elimination half-life, AUC0-48, AUC0-infinity, Cmax and Cmin were respectively 5.7 (0.3) h, 974 (107) ng/ml.h, 1022 (108) ng/ml.h, 102 (7) ng/ml and 43 (5) ng/ml. Exploratory statistics on the 13 volunteers common to both studies showed that the ratio of AUC desacetyl-diltiazem (DAD)/AUC diltiazem rose between single and multiple doses while elimination half-life of both diltiazem and N-desmethyl-diltiazem (MA), tmax, and AUC MA/AUC diltiazem were not affected. The conclusion of this study is that elimination half-life of diltiazem does not increase in elderly between single and multiple doses, possibly due to an increased biotransformation into DAD.