Effects of phenylbutazone on thiamylal disposition and anaesthesia in ponies

Phenylbutazone given during the perisurgical period has been reported to increase the intensity and duration of thiamylal anaesthesia in horses. A possible mechanism of competitive plasma protein binding has been suggested. The purpose of the present study was to experimentally reproduce the phenomenon of increased intensity and/or duration of thiamylal anaesthesia and to determine if there is competitive displacement of plasma protein bound thiamylal by phenylbutazone. Six ponies each received one of three treatments, 11 mg/kg intravenous (i.v.) thiamylal; 8.8 mg/kg i.v. phenylbutazone; and 11 mg/kg i.v. thiamylal with 8.8 mg/kg i.v. phenylbutazone given 9 min later. Thirteen blood samples were collected from 0 time through 600 min following drug administration and plasma drug concentrations quantified by high performance liquid chromatography. The pharmacokinetics of thiamylal and phenylbutazone were best described by three- and two-compartment models, respectively. There were no significant differences in pharmacokinetic parameters for thiamylal in the presence of phenylbutazone. However, there were differences in phenylbutazone pharmacokinetics when preceded by thiamylal administration. Unbound phenylbutazone concentrations were increased at 171, 231 and 351 min when given with thiamylal, accompanied by decreases in per cent bound phenylbutazone (P < 0.05). There were also significant (P < 0.05) changes in per cent plasma protein binding of thiamylal and phenylbutazone between 120 and 360 min, when in combination. No changes in intensity or duration of anaesthesia were observed.     

Pharmacokinetics of intravenous and oral methimazole following single-and multiple-dose administration in normal cats

The pharmacokinetics of methimazole (MMI) administered intravenously and orally were determined in six adult domestic shorthaired cats. There was no significant difference between mean serum MMI concentrations after oral and i.v. administration by 30 min post-MMI administration, indicating relatively rapid and complete absorption of the drug. The bioavailability of MMI ranged from 27% to 100% (mean = 81.1 +/- 11.4%). The mean serum elimination half-life was 6.6 +/- 2.0 h, with a wide range of values (1.9 h to 15.1 h). After repeat i.v. administration of MMI following 2 weeks of oral administration of the drug, no significant difference was found between mean serum concentrations after single-dose and multiple-dose administration. No significant change in serum elimination half-life or total body clearance was found after multiple-dose administration of MMI. Two cats with the longest half-lives (9.9 h and 15.1 h), however, did exhibit markedly shorter t1/2 values (3.5 h and 3.3 h, respectively) after multiple-dose administration. Values for central and steady state volumes of distribution also decreased after multiple-dose administration, possibly indicating saturation of thyroid uptake of MMI with chronic administration. These results indicate that MMI has good oral bioavailability and has a longer mean serum elimination half-life than propylthiouracil, the other anti-thyroid drug that has been evaluated in cats. Although no significant change in mean values occurred after multiple-dose administration of MMI, drug-induced acceleration of metabolism may occur in some cats after long-term MMI administration.     

Pharmacokinetics of phenylbutazone in plasma and milk of lactating dairy cows

Phenylbutazone was administered intravenously (i.v.) to a group of four lactating cows at a dosage of 6 mg/kg body weight. Whole plasma, protein-free plasma and milk were analysed for phenylbutazone residues. Pharmacokinetic parameters of total and free phenylbutazone in plasma were calculated using a non compartmental method. In regards to whole plasma data, the mean volume of distribution at steady state ( V _ss), was 147 mL/kg body weight, with a mean (± SEM) terminal elimination half-life ( t _1/2) of 40 ± 6 h. The mean clearance ( Cl ) was 3 mL/h/kg body weight. The V _ss as determined from the protein-free plasma fraction was 50 021 mL/kg body weight. This larger V _ss of free phenylbutazone compared to total plasma phenylbutazone was attributed to a high degree of plasma protein binding, as well as the greater penetration of free phenylbutazone into tissues. The mean t _1/2 of free phenylbutazone was 39 ± 5 h. This similarity to the t _1/2 estimated from total plasma phenylbutazone data is attributed to an equilibrium between free and plasma phenylbutazone during the terminal elimination phase. Mean t _1/2 as determined from milk, applying a urinary excretion rate model, was 47 ± 4 h. Milk clearance of phenylbutazone was 0.009 mL/h/kg body weight, or about 0.34% of total body clearance. Furthermore, evidence suggests that phenylbutazone either binds to milk proteins, or is actively transported into milk, as its concentration in milk was greater than that predicted due to a simple partitioning from plasma into milk.     

Nonlinear pharmacokinetics of intravenous sulphadimethoxine and its dosage regimen in pigs

The time courses of the total (Ct) and unbound plasma (Cf) concentration after the i.v. injection of 20, 50 and 100 mg/kg of sulphadimethoxine (SDM) were examined in pigs. The area under the Ct-time curve per unit dose decreased dose-dependently. Vdarea and total body clearance of Ct increased dose-dependently. The concentration-dependent plasma protein binding of SDM was evident after 50 and 100 mg/kg. The time courses of Cf en Ct after 3 doses were analyzed by a one compartment open model with nonlinear plasma protein binding. The agreement between calculated curves of Cf and Ct and the observed values, and relative constancy of pharmacokinetic parameters were obtained over 3 doses. These results suggested that the nonlinear pharmacokinetics of SDM was caused by saturable plasma protein binding. The multiple i.v. dose of SDM was based on the dosage regimen using the nonlinear pharmacokinetic model (50 mg/kg, 24 hour interval, 4 days). The observed Cf was maintained in the intended range by the dosage regimen. Therefore, the dosage regimen based on the nonlinear pharmacokinetics may allow the unbound concentration after i.v. injection of SDM in pigs to be controlled.     

Pharmacokinetics of phenylbutazone in beef steers

Phenylbutazone was administered intravenously to a group of 11 beef steers at a dosage of 6 mg/kg of body weight. Whole plasma and protein-free plasma were analyzed for phenylbutazone residues. Pharmacokinetic parameters of total and free phenylbutazone in plasma were calculated using a noncompartmental method. In regards to whole plasma data, the mean volume of distribution at steady state (Vss), was 140 mL/kg body weight, with a mean (+/-SEM) terminal elimination half-life (t1/2) of 34 +/- 9 h. The mean clearance was 3.2 mL/h/kg body weight. The Vss, as determined from the protein-free plasma fraction, was 54093 mL/kg body weight. This larger Vss of free phenylbutazone compared with total plasma phenylbutazone was attributed to a high degree of plasma protein binding, as well as the greater penetration of free phenylbutazone into tissues. The mean t1/2 of free phenylbutazone was 35 +/- 12 h. This similarity to the t1/2 estimated from total plasma phenylbutazone data is attributed to an equilibrium between free and plasma phenylbutazone during the terminal elimination phase. The pharmacokinetic parameters of free and total plasma phenylbutazone in beef steers are statistically similar to those previously reported for lactating dairy cows.     

Comparison of plasma and interstitial fluid concentrations of doxycycline and meropenem following constant rate intravenous infusion in dogs

OBJECTIVE: To compare plasma (total and unbound) and interstitial fluid (ISF) concentrations of doxycycline and meropenem in dogs following constant rate IV infusion of each drug. ANIMAL: 6 adult Beagles. PROCEDURE: Dogs were given a loading dose of doxycycline and meropenem followed by a constant rate IV infusion of each drug to maintain an 8-hour steady state concentration. Interstitial fluid was collected with an ultrafiltration device. Plasma and ISF were analyzed by high performance liquid chromatography. Protein binding and lipophilicity were determined. Plasma data were analyzed by use of compartmental methods. RESULTS: Compared with meropenem, doxycycline had higher protein binding (11.87% [previously published value] vs 91.75 +/- 0.63%) and lipophilicity (partition coefficients, 0.02 +/- 0.01 vs 0.68 +/- 0.05). A significant difference was found between ISF and plasma total doxycycline concentrations. No significant difference was found between ISF and plasma unbound doxycycline concentrations. Concentrations of meropenem in ISF and plasma (total and unbound) were similar. Plasma half-life, volume of distribution, and clearance were 4.56 +/- 0.57 hours, 0.65 +/- 0.82 L/kg, and 1.66 +/- 2.21 mL/min/kg, respectively, for doxycycline and 0.73 +/- 0.07 hours, 0.34 +/- 0.06 L/kg, and 5.65 +/- 2.76 mL/min/kg, respectively, for meropenem. The ISF half-life of doxycycline and meropenem was 4.94 +/- 0.67 and 2.31 +/- 0.36 hours, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: The extent of protein binding determines distribution of doxycycline and meropenem into ISF. As a result of high protein binding, ISF doxycycline concentrations are lower than plasma total doxycycline concentrations. Concentrations of meropenem in ISF can be predicted from plasma total meropenem concentrations.     

Plasma concentrations of praziquantel after oral administration of single and multiple doses in loggerhead sea turtles (Caretta caretta)

OBJECTIVE: To determine the pharmacokinetics of praziquantel following single and multiple oral dosing in loggerhead sea turtles. ANIMALS: 12 healthy juvenile loggerhead sea turtles. PROCEDURE: Praziquantel was administered orally as a single dose (25 and 50 mg/kg) to 2 groups of turtles; a multiple-dose study was then performed in which 6 turtles received 3 doses of praziquantel (25 mg/kg, PO) at 3-hour intervals. Blood samples were collected from all turtles before and at intervals after drug administration for assessment of plasma praziquantel concentrations. Pharmacokinetic analyses included maximum observed plasma concentration (Cmax), time to maximum concentration (Tmax), area under the plasma praziquantel concentration-time curve, and mean residence time (MRTt). RESULTS: Large interanimal variability in plasma praziquantel concentrations was observed for all dosages. One turtle that received 50 mg of praziquantel/kg developed skin lesions within 48 hours of administration. After administration of 25 or 50 mg of praziquantel/kg, mean plasma concentrations were below the limit of quantification after 24 hours. In the multiple-dose group of turtles, mean plasma concentration was 90 ng/mL at the last sampling time-point (48 hours after the first of 3 doses). In the single-dose study, mean Cmax and Tmax with dose were not significantly different between doses. After administration of multiple doses of praziquantel, only MRTt was significantly increased, compared with values after administration of a single 25-mg dose. CONCLUSIONS AND CLINICAL RELEVANCE: Oral administration of 25 mg of praziquantel/kg 3 times at 3-hour intervals may be appropriate for treatment of loggerhead sea turtles with spirorchidiasis.     

Effects of oral cimetidine on plasma concentrations of phenylbutazone in horses

Phenylbutazone was administered to six Thoroughbred horses in a cross-over study in which the horses received cimetidine pretreatment or no cimetidine pretreatment. Blood samples were collected at various times for 48 h after phenylbutazone administration and the plasma was analysed for phenylbutazone. Cimetidine pretreatment elevated phenylbutazone plasma concentrations during the first 8 h after phenylbutazone administration. The absorption rate, maximum phenylbutazone plasma concentrations and AUC were significantly greater with cimetidine pretreatment. The half-life of phenylbutazone did not change with cimetidine pretreatment; however, lower plasma concentrations of the metabolite gamma-hydroxyphenylbutazone were observed with cimetidine pretreatments. Plasma concentrations of the metabolite oxyphenbutazone were unchanged with cimetidine pretreatment compared to control values. Twenty-four-hour plasma concentrations of phenylbutazone were not different from control values with cimetidine pretreatment. This study suggests that concurrent treatment with cimetidine and phenylbutazone 24 h before race time does not result in elevations of plasma phenylbutazone concentrations above control values.     

Pharmacokinetics of orally administered phenylbutazone in African and Asian elephants (Loxodonta africana and Elephas maximus)

The pharmacokinetic parameters of phenylbutazone were determined in 18 elephants (Loxodonta africana and Elephas maximus) after single-dose oral administration of 2, 3, and 4 mg/kg phenylbutazone, as well as multiple-dose administrations with a 4-wk washout period between trials. After administration of 2 mg/kg phenylbutazone, mean serum concentrations peaked in approximately 7.5 hr at 4.3 +/- 2.02 microg/ml and 9.7 hr at 7.1 +/- 2.36 microg/ml for African and Asian elephants, respectively, while 3 mg/kg dosages resulted in peak serum concentrations of 7.2 +/- 4.06 microg/ml in 8.4 hr and 12.1 +/- 3.13 microg/ml in 14 hr. The harmonic mean half-life was long, ranging between 13 and 15 hr and 39 and 45 hr for African and Asian elephants, respectively. There was evidence of enterohepatic cycling of phenylbutazone in Asian elephants. Significant differences (P < 0.0001) in pharmacokinetic values occurred between African and Asian elephants for clearance (27.9 and 7.6 ml/hr/kg, respectively), terminal half-life (15.0 and 38.7 hr, respectively), and mean residence time (22.5 and 55.5 hr, respectively) using 2-mg/kg dosages as an example. This suggests that different treatment regimens for Asian and African elephants should be used. There were no apparent gender differences in these parameters for either elephant species.     

Pharmacokinetics of cefovecin in cats

The pharmacokinetics of the novel cephalosporin cefovecin were investigated in a series of in vivo, ex vivo and in vitro studies following administration to adult cats at 8 mg/kg bodyweight. Bioavailability and pharmacokinetic parameters were determined in a cross-over study after intravenous (i.v.) and subcutaneous (s.c.) injections. [14C]cefovecin was used to evaluate excretion for 21 days after s.c. administration. Protein binding was determined in vitro in feline plasma and ex vivo in transudate from cats surgically implanted with tissue chambers. After s.c. administration, cefovecin was characterized by rapid absorption with mean peak plasma concentrations of 141+/-12 microg/mL being achieved within 2 h of s.c. injection with full bioavailability (99%). The mean elimination half-life was 166+/-18 h. After i.v. administration, volume of distribution was 0.09+/-0.01 L/kg and mean plasma clearance was 0.35+/-0.04 mL/h/kg. Approximately 50% of the administered radiolabelled dose was eliminated over the 21-day postdose period via urinary excretion and up to approximately 25% in faeces. In vitro and ex vivo plasma protein binding ranged from 99.8% to 99.5% over the plasma concentration range 10-100 microg/mL. Ex vivo protein binding in transudate was as low as 90.7%. From 8 h postdose, concentrations of unbound (free) cefovecin in transudate were consistently higher than in plasma, with mean unbound cefovecin concentrations being maintained above 0.06 microg/mL (MIC90 of Pasteurella multocida) in transudate for at least 14 days postdose. The slow elimination and long-lasting free concentrations in extracellular fluid are desirable pharmacokinetic attributes for an antimicrobial with a 14-day dosing interval.     

Pharmacokinetic studies of phenylbutazone in cattle

The disposition kinetics and systemic availability of phenylbutazone were studied in healthy dairy cows. The same dose (6mg/kg) of phenylbutazone was administered by the i.v., i.m. and oral routes. The elimination half time after intravenous administration ranged from 32.4 to 60.8h. The result suggested that the distribution of phenylbutazone in cows can be described by a two-compartment open model. Total body clearance of the drug had a mean value of 0.0016 ml/kg-h. The overall tissue to plasma level ratio (k₁₂/k₂₁-β), after distribution equilibrium had been attained was 0.64. Phenylbutazone was shown, by an equilibrium dialysis method, to be highly bound to plasma proteins (93%) at serum levels of 100 μ/ml. The systemic availability of phenylbutazone was 69% and 89% when administered orally and intramuscularly respectively. Animals receiving half the dose of phenylbutazone (3 mg/kg) intravenously did not differ from cows receiving 6 mg/kg in elimination half-life and other distribution and elimination kinetic parameters. Based on the experimental data obtained, a dosage regimen is proposed, consisting of a priming oral dose of 9 mg/kg and maintenance doses of 4.5 mg/kg of phenylbutazone orally administered at 48 h intervals. The relatively long half-life in cattle, however, complicates the use of phenylbutazone because of the drug residue problem.     

Carprofen pharmacokinetics in plasma and in control and inflamed canine tissue fluid using in vivo ultrafiltration

Measurement of unbound drug concentrations at their sites of action is necessary for accurate PK/PD modeling. The objective of this study was to determine the unbound concentration of carprofen in canine interstitial fluid (ISF) using in vivo ultrafiltration and to compare pharmacokinetic parameters of free carprofen concentrations between inflamed and control tissue sites. We hypothesized that active concentrations of carprofen would exhibit different dispositions in ISF between inflamed vs. normal tissues. Bilateral ultrafiltration probes were placed subcutaneously in six healthy Beagle dogs 12 h prior to induction of inflammation. Two milliliters of either 2% carrageenan or saline control was injected subcutaneously at each probe site, 12 h prior to intravenous carprofen (4 mg/kg) administration. Plasma and ISF samples were collected at regular intervals for 72 h, and carprofen concentrations were determined using HPLC. Prostaglandin E2 (PGE₂) concentrations were quantified in ISF using ELISA. Unbound carprofen concentrations were higher in ISF compared with predicted unbound plasma drug concentrations. Concentrations were not significantly higher in inflamed ISF compared with control ISF. Compartmental modeling was used to generate pharmacokinetic parameter estimates, which were not significantly different between sites. Terminal half‐life (T½) was longer in the ISF compared with plasma. PGE₂ in ISF decreased following administration of carprofen. In vivo ultrafiltration is a reliable method to determine unbound carprofen in ISF, and that disposition of unbound drug into tissue is much higher than predicted from unbound drug concentration in plasma. However, concentrations and pharmacokinetic parameter estimates are not significantly different in inflamed vs. un‐inflamed tissues.     

Pharmacokinetics of voriconazole after oral administration of single and multiple doses in African grey parrots (Psittacus erithacus timneh)

OBJECTIVE: To determine the pharmacokinetics and safety of orally administered voriconazole in African grey parrots. ANIMALS: 20 clinically normal Timneh African grey parrots (Psittacus erithacus timneh). PROCEDURES: In single-dose trials, 12 parrots were each administered 6, 12, and 18 mg of voriconazole/kg orally and plasma concentrations of voriconazole were determined via high-pressure liquid chromatography. In a multiple-dose trial, voriconazole (18 mg/kg) was administered orally to 6 birds every 12 hours for 9 days; a control group (2 birds) received tap water. Treatment effects were assessed via observation, clinicopathologic analyses (3 assessments), and measurement of trough plasma voriconazole concentrations (2 assessments). RESULTS: Voriconazole's elimination half-life was short (1.1 to 1.6 hours). Higher doses resulted in disproportional increases in the maximum plasma voriconazole concentration and area under the curve. Trough plasma voriconazole concentrations achieved in the multiple-dose trial were lower than those achieved after administration of single doses. Polyuria (the only adverse treatment effect) developed in treated and control birds but was more severe in the treatment group. CONCLUSIONS AND CLINICAL RELEVANCE: In African grey parrots, voriconazole has dose-dependent pharmacokinetics and may induce its own metabolism. Oral administration of 12 to 18 mg of voriconazole/kg twice daily is a rational starting dose for treatment of African grey parrots infected with Aspergillus or other fungal organisms that have a minimal inhibitory concentration for voriconazole < or = 0.4 microg/mL. Higher doses may be needed to maintain plasma voriconazole concentrations during long-term treatment. Safety and efficacy of various voriconazole treatment regimens in this species require investigation.     

Plasma concentration, mammary excretion and side-effects of phenylbutazone after repeated oral administration in healthy cows

Seven clinically healthy dairy cows were each given 2.5 gphenylbutazone (approximately 5 mg/kg body weight) by oral administration twice daily for 8 days. The concentrations of phenylbutazone in plasma and milk and several blood parameters were studied. The minium plasma concentration during steady state was 100.4 ± 7.3 μg/ml. During the same period the milk concentration never exceeded 1% of the plasma concentration. The elimination half-life in plasma was 38.6 ± 3.7 h. Five days after administration had been discontinued, the milk concentration was 0.05 ± 0.01 μg/ml. All seven cows were clinically healthy throughout the experiment. The most pronounced side-effect of the blood parameters studied was a decreased concentration of leucocytes to about two-thirds of the control value. This might have a pronounced influence on the effectiveness of the immune system. There was also a significant decrease in total bilirubin indicating a decrease in the breakdown of erythrocytes.     

盐酸环丙沙星在子宫内膜炎奶牛乳腺排泄的研究

通过子宫内灌注盐酸环丙沙星,采用内标法以反相高效液相色谱法测定了4头患子宫内膜炎的奶牛乳汁中盐酸环丙沙星的药物浓度。研究表明,在奶牛给药后0 h~24 h,血药浓度大于乳药浓度,在24 h后,乳药浓度大于血药浓度。在48 h内盐酸环丙沙星的乳药浓度值均高于MIC值,所以仍具有抑菌作用,这对乳房炎的治疗具有重要意义。     

Pharmacokinetics of phenylbutazone in two age groups of ponies: a preliminary study

A clinical dose rate (4.4 mg/kg bodyweight) of phenylbutazone was administered intravenously and orally to six Welsh mountain ponies to provide data on the pharmacokinetics and bioavailability of the drug. In three, three-year-old ponies, clearance of the drug from plasma after intravenous administration was almost twice as rapid as in three ponies aged eight to 10 years. After oral administration, plasma phenylbutazone levels were greater in the older ponies, the area under the plasma concentration time curve being almost twice as high. This did not result from more efficient absorption but from slower plasma clearance. The fractional absorption of phenylbutazone was similar in young and older ponies, 0.78 and 0.75, respectively. The 24 hour urinary excretion of phenylbutazone and its hydroxylated metabolites, oxyphenbutazone and gamma-hydroxyphenylbutazone, accounted for approximately 25 per cent of the administered intravenous dose in both young and older ponies. The possible fate(s) of the remaining 75 per cent were considered.     

Pharmacokinetics of meloxicam in plasma and urine of horses

OBJECTIVE: To determine pharmacokinetic parameters for meloxicam, a nonsteroidal anti-inflammatory drug, in horses. ANIMALS: 8 healthy horses. PROCEDURE: In the first phase of the study, horses were administered meloxicam once in accordance with a 2 x 2 crossover design (IV or PO drug administration; horses fed or not fed). The second phase used a multiple-dose regimen (daily oral administration of meloxicam for 14 days), with meloxicam administered at the recommended dosage (0.6 mg/kg). Plasma and urine concentrations of meloxicam were measured by use of validated methods with a limit of quantification of 10 ng/mL for plasma and 20 ng/mL for urine. RESULTS: Plasma clearance was low (mean +/- SD; 34 +/- 0.5 mL/kg/h), steady-state volume of distribution was limited (0.12 +/- 0.018 L/kg), and terminal half-life was 8.54 +/- 3.02 hours. After oral administration, bioavailability was nearly total regardless of feeding status (98 +/- 12% in fed horses and 85 +/- 19% in nonfed horses). During once-daily administration for 14 days, we did not detect drug accumulation in the plasma. Meloxicam was eliminated via the urine with a urine-to-plasma concentration that ranged from 13 to 18. Concentrations were detected for a relatively short period (3 days) after administration of the final daily dose. CONCLUSIONS AND CLINICAL RELEVANCE: Results of this study support once-daily administration of meloxicam regardless of the feeding status of a horse and suggest a period of at least 3 days before urine concentrations of meloxicam reach concentrations that could be used in drug control programs.     

The influence of furosemide on plasma elimination and urinary excretion of drugs in standardbred horses

A study of the effects of intravenous administration of either 150 mg or 250 mg of furosemide to standardbred mares pre-treated with other drugs was undertaken to determine whether a unique pattern of drug elimination into urine and from plasma for each compound occurred. Furosemide significantly reduced the plasma concentrations of codeine compared to control 2-6 h after furosemide administration. In contrast, the plasma concentrations of theophylline, phenylbutazone, pentazocine, guaifenesin and flunixin were not markedly altered by furosemide. In the case of acepromazine, clenbuterol and fentanyl, the data generated were insufficient to state with certainty whether or not furosemide affected the plasma concentrations of these three drugs. A significant reduction was noted in the urinary concentrations of guaifenesin, acepromazine, clenbuterol, phenylbutazone, flunixin, fentanyl and pentazocine within 1-4 h of furosemide administration. The urinary concentrations of theophylline remained reduced as long as 8 h after furosemide injection. Furosemide administration to horses pre-treated with codeine resulted in depression of urinary morphine concentrations 2-4 h and 9-12 h after furosemide injection. A lower furosemide dose (150 mg) produced changes in drug urinary excretion and plasma elimination equivalent to the higher dose (250 mg). It is evident that furosemide affects the urinary and plasma concentrations of other co-administered drugs but not in a predictable fashion, which limits the extrapolation of these results to as yet untested drugs.     

Oral dosage regimen in the nonlinear pharmacokinetics of sulphadimethoxine in pigs

An oral high dosage regimen of sulphadimethoxine (SDM) was examined in pigs. The dose (50 mg/kg) in the therapeutic range, showed nonlinear pharmacokinetics, and administered by drench once a day for 4 days. The unbound plasma concentration-time profile was compared with that of the dosage regimen based on nonlinear pharmacokinetics, where a pharmacokinetic model and parameters were used except for the first order absorption rate constant (ka) and bioavailability (F). F and ka were obtained from oral and intravenous administration of 20 and 10 mg/kg of SDM. The unbound plasma concentration was observed almost within the setting range by the dosage regimen through the experimental period. This result suggested that the dosage regimen, based on the nonlinear pharmacokinetic model, resulted in an appropriate effect in the clinical use.