Pharmacokinetics of probenecid and the effect of oral probenecid administration on the pharmacokinetics of cefazolin in mares

The pharmacokinetics and bioavailability of probenecid given IV and orally at the dosage level of 10 mg/kg of body weight to mares were investigated. Probenecid given IV was characterized by a rapid disposition phase with a mean half-life of 14.0 minutes and a subsequent slower elimination phase with a mean half-life of 87.8 minutes in 5 of 6 mares. In the remaining mare, a rapid disposition phase was not observed, and the half-life of the elimination phase was slower (172 minutes). The mean residence time of probenecid averaged 116 minutes for all 6 mares and 89.2 minutes for the 5 mares with biphasic disposition. The total plasma clearance of probenecid averaged 1.18 +/- 0.49 ml/min/kg, whereas renal clearance accounted for 42.6 +/- 9.3% of the total clearance. The steady-state volume of distribution of probenecid averaged 116 +/- 28.2 ml/kg. Plasma protein binding of probenecid was extensive, with 99.9% of the drug bound at plasma probenecid concentrations of 10 micrograms/ml. The maximum plasma probenecid concentration after 10 mg/kg orally averaged nearly 30 micrograms/ml. The half-life of probenecid after oral administration was approximately 120 minutes. Oral bioavailability was good with greater than 90% of the dose absorbed. The effect of probenecid on tubular secretion of organic anions was evaluated by determining the pharmacokinetics of IV cefazolin (11 mg/kg) administered alone and 15 minutes after probenecid (10 mg/kg orally). Treatment with probenecid did not affect pharmacokinetic values of cefazolin. This failure of probenecid to alter the pharmacokinetics of cefazolin may be caused by insufficient plasma probenecid concentrations after the oral dose.     

Pharmacokinetics and body fluid and endometrial concentrations of cephapirin in mares

Six healthy adult horse mares were each given a single injection of sodium cephapirin (20 mg/kg of body weight, IV), and serum cephapirin concentrations were measured serially over a 6-hour period. The mean elimination rate constant was 0.78 hour-1 and the elimination half-life was 0.92 hours. The apparent volume of distribution (at steady state) and the clearance of the drug were estimated at 0.17 L/kg and 598 ml/hour/kg, respectively. Each mare was then given 4 consecutive IM injections of sodium cephapirin (400 mg/ml) at a dosage level of 20 mg/kg. Cephapirin concentrations in serum, synovial fluid, peritoneal fluid, CSF, urine, and endometrium were measured serially. After IM administration, the highest mean serum concentration was 14.8 micrograms/ml 25 minutes after the 4th injection. The highest mean synovial and peritoneal concentrations were 4.6 micrograms/ml and 5.0 micrograms/ml, respectively, 2 hours after the 4th injection. The highest mean endometrial concentration was 2.2 micrograms/g 4 hours after the 4th injection. Mean urine concentrations reached 7,421 micrograms/ml. Cephapirin did not readily penetrate the CSF. When cephapirin was given IM at the same dose, but in a less concentrated solution (250 mg/ml), serum concentrations peaked at 25.0 micrograms/ml 20 minutes after injection, but the area under the serum concentration-time curve was not significantly different (P greater than 0.05). The bioavailability of the drug was greater than or equal to 95% after IM injection.     

Serum concentrations and pharmacokinetics of enrofloxacin after intravenous and intragastric administration to mares.

Serum concentrations and pharmacokinetics of enrofloxacin were studied in 6 mares after intravenous (IV) and intragastric (IG) administration at a single dose rate of 7.5 mg/kg body weight. In experiment 1, an injectable formulation of enrofloxacin (100 mg/mL) was given IV. At 5 min after injection, mean serum concentration was 9.04 microg/mL and decreased to 0.09 microg/mL by 24 h. Elimination half-life was 5.33 +/- 1.05 h and the area under the serum concentration vs time curve (AUC) was 21.03 +/- 5.19 mg x h/L. In experiment 2, the same injectable formulation was given IG. The mean peak serum concentration was 0.94 +/- 0.97 microg/mL at 4 h after administration and declined to 0.29 +/- 0.12 microg/mL by 24 h. Absorption of this enrofloxacin preparation after IG administration was highly variable, and for this reason, pharmacokinetic values for each mare could not be determined. In experiment 3, a poultry formulation (32.3 mg/mL) was given IG. The mean peak serum concentration was 1.85 +/- 1.47 microg/mL at 45 min after administration and declined to 0.19 +/- 0.06 microg/mL by 24 h. Elimination half-life was 10.62 +/- 5.33 h and AUC was 16.30 +/- 4.69 mg x h/L. Bioavailability was calculated at 78.29 +/- 16.55%. Minimum inhibitory concentrations of enrofloxacin were determined for equine bacterial culture specimens submitted to the microbiology laboratory over an 11-month period. The minimum inhibitory concentration of enrofloxacin required to inhibit 90% of isolates (MIC90) was 0.25 microg/mL for Staphylococcus aureus, Escherichia coli, Salmonella spp., Klebsiella spp., and Pasteurella spp. The poultry formulation was well tolerated and could be potentially useful in the treatment of susceptible bacterial infections in adult horses. The injectable enrofloxacin solution should not be used orally.     

Amikacin sulfate in mares: pharmacokinetics and body fluid and endometrial concentrations after repeated intramuscular administration

Six mares were given 5 IM injections (at 12-hour intervals between doses) of amikacin sulfate at a dosage of 7 mg/kg of body weight. Serum amikacin concentrations were measured serially throughout the study; synovial, peritoneal, endometrial, and urine concentrations were determined after the last injection. Amikacin concentrations of the CSF were measured serially in 3 of the 6 mares; 1 of the 3 mares had septic meningitis. Mean serum amikacin concentrations peaked at 1 to 2 hours after IM injection. The highest mean serum concentration was 19.2 micrograms/ml (1.5 hours after the 5th injection). The highest mean synovial concentration was 10.8 micrograms/ml at 2 hours after the 5th injection; the highest mean peritoneal concentration was 16.2 micrograms/ml at 3 hours after the 5th injection. The mean endometrial amikacin concentration was 2.5 micrograms/g (1.5 hours after the 5th injection). Amikacin reached a CSF concentration of 0.97 micrograms/ml in the mare with meningitis, but amikacin was not detected in CSF of healthy mares. Urine concentrations reached 1,458 micrograms/ml. Pharmacokinetic values were estimated after the 1st injection (elimination rate constant = 0.31/hour; half-life = 2.3 hours; apparent volume of distribution = 0.26 L/kg), and after the 5th injection (elimination rate constant = 0.28/hour; half-life = 2.6 hours; apparent volume of distribution = 0.30 L/kg); significant differences were not observed.     

Effect of probenecid on the pharmacokinetics of cefotaxime in sheep

The effect of probenecid given by intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) injection on the pharmacokinetics of cefotaxime was studied in six Merino ewes. When given intravenously, probenecid increased significantly (P less than 0.05) the plasma half-life of cefotaxime three-fold (to 0.94 +/- 0.32 h) and the area under the curve (AUC) approximately two-fold (to 41.1 +/- 16.8 micrograms.h/ml), and decreased plasma cefotaxime clearance (ClB) 45% (to 0.648 +/- 0.191 l/h/kg). When given with probenecid intravenously, renal clearance (ClR), volume of the central compartment (VC), volume of distribution steady state (Vd(ss], and the amount excreted in urine unchanged did not alter significantly. When given by i.m. injection, probenecid and cefotaxime were well tolerated and cefotaxime was well absorbed (101 +/- 45%). When given by s.c. injection, only 40 +/- 25% cefotaxime was absorbed. When given intramuscularly or subcutaneously, probenecid appeared to reduce the ClB and ClR of cefotaxime, probably because plasma probenecid concentrations are prolonged. Probenecid did not appear to affect the distribution of cefotaxime.     

Effect of milk fraction on concentrations of cephapirin and desacetylcephapirin in bovine milk after intramammary infusion of cephapirin sodium

Clinical mastitis in dairy cows is commonly treated with intramammary (IMM) antimicrobial agents. Pharmacokinetic data are used to design treatment regimens and determine withholding times. In some pharmacokinetic studies, investigators measure antimicrobial concentrations in foremilk, whereas in others, they use bucket milk or do not specify the milk fraction sampled. Our objective was to compare antimicrobial concentrations in foremilk, bucket milk, and strippings after IMM treatment of six healthy Holsteins. One mammary gland/cow was infused with 200 mg of cephapirin (CEPH) after each of the two milkings, using different milking frequencies and treatment intervals in a randomized crossover design. Treated glands were sampled at the first milking following each infusion. Antimicrobial concentrations in milk were measured using HPLC/MS/MS. CEPH concentration was higher in foremilk (geometric mean 44.2 μg/mL) than in bucket milk (15.7 μg/mL) or strippings (18.5 μg/mL), as it was true for desacetylcephapirin (DAC) (59.5, 23.0, and 30.2 μg/mL, respectively). This finding, which was based on milk samples collected at the first milking after IMM infusion, suggests that pharmacokinetic data based on drug concentrations in foremilk may be misleading. Strippings were more representative of bucket milk than foremilk. The relationship between milk fraction and antimicrobial concentration should be investigated for other IMM antimicrobial agents. Meanwhile, it is essential that pharmacokinetic and residue studies report the fraction of milk that was analyzed.     

Pharmacokinetics and serum concentrations of cephapirin in neonatal foals

Six healthy foals, from 4 to 6 days of age, were given a single IM injection of sodium cephapirin (250 mg/ml) at a rate of 20 mg/kg of body weight. Serum concentrations of cephapirin were measured serially over an 8-hour period. The mean peak serum concentration was 21.2 micrograms/ml at 10 minutes. The overall elimination rate constant was 1.06/hr and the elimination half-life was 0.70 hour. The apparent volume of distribution at steady state was 1.06 L/kg and plasma clearance was 1,105 ml/hr/kg.     

Combined pharmacokinetics of gentamicin in pony mares after a single intravenous and intramuscular administration

Healthy mature pony mares (n = 6) were given a single dose of gentamicin (5 mg/kg of body weight) IV or IM 8 days apart. Venous blood samples were collected at 0, 5, 10, 20, 30, and 45 minutes and at 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 18, 24, 30, 36, 40, and 48 hours after IV injection of gentamicin, and at 10, 20, 30, and 45 minutes and at 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 18, 24, and 30 hours after IM injection of gentamicin. Gentamicin serum concentration was determined by a liquid-phase radioimmunoassay. The combined data of IV and IM treatments were analyzed by a nonlinear least-square regression analysis program. The kinetic data were best fitted by a 2-compartment open model, as indicated by residual trends and improvements in the correlation of determination. The distribution phase half-life was 0.12 +/- 0.02 hour and postdistribution phase half-life was 1.82 +/- 0.22 hour. The volume of the central compartment was 115.8 +/- 6.0 ml/kg, volume of distribution at steady state was 188 +/- 9.9 ml/kg, and the total body clearance was 1.27 +/- 0.18 ml/min/kg. Intramuscular absorption was rapid with a half-life for absorption of 0.64 +/- 0.14 hour. The extent of absorption was 0.87 +/- 0.14. Kinetic calculations predicted that IM injections of 5 mg of gentamicin/kg every 8 hours would provide average steady-state serum concentrations of 7.0 micrograms/ml, with maximum and minimum steady-state concentrations of 16.8 and 1.1 micrograms/ml, respectively.     

Effect of transportation on the estrous cycle and concentrations of hormones in mares

Effect of transportation on estrous behavior, duration of the estrous cycle, ovulation, pregnancy rates and concentrations of serum cortisol, plasma ascorbic acid (AA), LH, estradiol and progesterone in mares was investigated. Fifteen mares were transported for 792 km (12 h) during the preovulatory stage of estrus. Transported mares were bled immediately before transport (baseline), at midtrip and 0, 12, 24, 48 and 72 h post-transport and twice daily from d 1 before transport to d 1 (estrogen) or 3 (LH) post-ovulation. Blood samples also were taken for progesterone on d 0, 2, 6, 10, 15, 16, 17, 18, 19 and 20 post-ovulation. Nontransported control mares (n = 15) were bled on the same schedule as transported mares. There was no difference (P greater than .05) in number of mares ovulating, estrous behavior, duration of the estrous cycle or pregnancy rate between groups. Cortisol in transported mares increased to concentrations greater (P less than .05) than those in control mares at midtrip and 0 h post-transport. Concentrations of AA in transported mares also increased (P less than .05) at midtrip, then decreased (P less than .05) below baseline at 24 h post-transport. Concentrations of LH and estradiol increased (P less than .05) above baseline throughout the blood-sampling period. Increases apparently were due to preovulatory surges of these hormones. Increase in LH concentrations in transported mares, however, was greater (P less than .05) than that in control mares at 0 h post-transport.(ABSTRACT TRUNCATED AT 250 WORDS)     

Elevation and prolongation of serum ampicillin and amoxycillin concentrations in calves by the concomitant administration of probenecid

The effects of probenecid on serum ampicillin and amoxycillin concentrations were investigated in 1–5 week old calves after oral and parenteral drug administration. Ampicillin trihydrate was administered orally at 250mg/calf, after an overnight fast, alone and with 1.5g probenecid. Peak serum ampicillin concentrations were elevated from 0.60 to 1.22 μg/ml by the co-administration of probenecid. In calves given 0.5 g amoxycillin trihydrate with the milk replacer, peak serum drug concentration increased from 1.74 to 3.16 μg/ml when 1.5 g probenecid was given too. Maximal effect of probenecid administered orally was with the 1.5 g/calf dose with considerably lesser increase in peak serum amoxycillin being observed with doses of 0.5 g, 1 g and 2 g/calf. After parenteral injection of probenecid solution at 1 g and 2 g/calf serum ampicillin concentrations peaked at more than twice the concentrations measured after equal doses of the two antibiotics were injected alone. The co-administration of 2 g probenecid and 1 g sodium ampicillin or 0.5 g sodium amoxycillin parenterally resulted in peak antibiotic concentrations considered to be effective against some of the more resistant pathogenic Gram-negative bacteria associated with diseases in calves and serum antibiotic concentrations 5 μg/ml were maintained during 5–6 h as opposed to 2–3 h after the antibiotics were injected alone. Oral administration of 1.5 g probenecid at three consecutive milk feeding times did not alter serum urea or serum creatinine concentrations.     

Body fluid concentrations and pharmacokinetics of chloramphenicol given to mares intravenously or by repeated gavage

Serum concentrations and the pharmacokinetics of chloramphenicol were determined in 6 healthy mares after a single IV administration (50 mg/kg of body weight) or after the 1st and 5th sequential intragastric (IG) administration (50 mg/kg/6 hours) of chloramphenicol. Synovial fluid, peritoneal fluid, CSF, and urinary concentrations of chloramphenicol after the IG administrations also were determined. Mean (+/- SEM) overall elimination rate constant (K) values for the IV, 1st IG, and 5th IG dosages were 0.42 +/- 0.064/hr, 0.42 +/- 0.049/hr, and 0.29 +/- 0.074/hr, respectively, and were not significantly different from one another (P greater than 0.05). Bioavailability was 40 +/- 8.6% after the 1st IG administration and was 21 +/- 5.2% after the 5th IG administration. Values for the area under the curve (AUC) for the 1st and 5th IG dosages were significantly different from the AUC value for the IV dosage, and the AUC value for the 5th IG dosage was significantly different from that for the 1st IG dosage. Chloramphenicol was administered to 2 mares in 6 consecutive doses; the first and last doses were given IV and the others were given IG. Mean K values after the 2 IV doses were 0.38 +/- 0.112/hr and 0.56 +/- 0.078/hr, which were not significantly different from each other or from the mean value for the IV dosage given to all 6 mares. Absorption of chloramphenicol decreased with repeated IG administrations, resulting in lower concentrations of chloramphenicol with subsequent administrations. Five consecutive IG doses of chloramphenicol were administered to 4 of the mares in a separate experiment and did not alter intestinal xylose absorption.     

Tissue and serum concentrations of amikacin after intramuscular and intrauterine administration to mares in estrus.

Concentrations of amikacin in endometrial tissue and plasma were studied in mares in estrus after intrauterine infusion of 1.0 or 2.0 g once a day for 3 consecutive d, and after 9.7 or 14.5 mg/kg body weight (BW) had been injected intramuscularly once a day for 3 consecutive d to determine concentrations of amikacin sulfate in plasma and endometrial tissues, and whether parenteral administration provides any advantages over intramuscular infusion. No amikacin was detected in serum at the 1.0 g dose. At the infusion dose of 2.0 g once a day, very low levels of serum amikacin were detected at 1 and 4 h postinfusion on the 1st treatment day. Amikacin was found to penetrate the endometrium after intramuscular injection; however, the levels attained were not as high as those achieved following intrauterine infusion. Based on the tissue and serum concentrations of amikacin, an intrauterine infusion at a dose of 4.4 mg/kg BW/d would appear to be an appropriate therapeutic regimen for the treatment of gram-negative endometritis.     

Pharmacokinetics and synovial fluid concentrations of cephapirin in calves with suppurative arthritis

Six calves with suppurative arthritis were given a single IM injection of sodium cephapirin at a dosage of 10 mg/kg of body weight. Cephapirin concentrations were serially measured in serum and in normal and suppurative synovial fluid over a 24-hour period. Mean peak serum concentration was 6.33 microliters/ml at 20 minutes after injection. The highest cephapirin concentrations in normal and suppurative synovial fluid were 1.68 and 1.96 micrograms/ml, respectively, 30 minutes after injection. Overall mean cephapirin concentration in normal synovial fluid for the first 4 hours (1.04 +/- 0.612 micrograms/ml) was not significantly different from that in suppurative synovial fluid (0.88 +/- 0.495 micrograms/ml; P greater than 0.05). Elimination half-life was 0.60 hours and clearance was 1,593 ml/h/kg.     

Plasma pharmacokinetics and tissue fluid concentrations of meropenem after intravenous and subcutaneous administration in dogs

OBJECTIVE: To estimate pharmacokinetic variables and measure tissue fluid concentrations of meropenem after IV and SC administration in dogs. ANIMALS: 6 healthy adult dogs. PROCEDURE: Dogs were administered a single dose of meropenem (20 mg/kg) IV and SC in a crossover design. To characterize the distribution of meropenem in dogs and to evaluate a unique tissue fluid collection method, an in vivo ultrafiltration device was used to collect interstitial fluid. Plasma, tissue fluid, and urine samples were analyzed by use of high-performance liquid chromatography. Protein binding was determined by use of an ultrafiltration device. RESULTS: Plasma data were analyzed by compartmental and noncompartmental pharmacokinetic methods. Mean +/- SD values for half-life, volume of distribution, and clearance after IV administration for plasma samples were 0.67 +/- 0.07 hours, 0.372 +/- 0.053 L/kg, and 6.53 +/- 1.51 mL/min/kg, respectively, and half-life for tissue fluid samples was 1.15 +/- 0.57 hours. Half-life after SC administration was 0.98 +/- 0.21 and 1.31 +/- 0.54 hours for plasma and tissue fluid, respectively. Protein binding was 11.87%, and bioavailability after SC administration was 84%. CONCLUSIONS AND CLINICAL RELEVANCE: Analysis of our data revealed that tissue fluid and plasma (unbound fraction) concentrations were similar. Because of the kinetic similarity of meropenem in the extravascular and vascular spaces, tissue fluid concentrations can be predicted from plasma concentrations. We concluded that a dosage of 8 mg/kg, SC, every 12 hours would achieve adequate tissue fluid and urine concentrations for susceptible bacteria with a minimum inhibitory concentration of 0.12 microg/mL.     

Testosterone administration to mares during estrus: duration of estrus and diestrus and concentrations of LH and FSH in plasma

To study the possible role of ovarian androgens in regulation of follicle stimulating hormone (FSH) secretion in the cycling mare, five mature, intact mares were treated with testosterone (20 micrograms/kg of body weight) daily during estrus; five control mares received safflower oil on the same schedule. Mares were teased for estrus and samples of jugular blood were drawn daily through one full estrous cycle. Concentrations of FSH in plasma were measured by a newly developed radioimmunoassay based on anti-ovine FSH serum and radioiodinated equine FSH. Testosterone treatment during estrus had no effect on duration of estrus, diestrus or the total cycle. Concentrations of FSH in plasma during estrus were unaffected by testosterone treatment. However, FSH concentrations in testosterone-treated mares were elevated (P less than .05) compared with controls during mid-diestrus (d 6 through 11). The magnitude and timing of the LH peaks were unaffected by treatment, as was the day on which the first elevated progesterone concentration occurred. These data are consistent with a model of FSH secretion in which ovarian androgens cause an accumulation of FSH in the pituitary during estrus in preparation for the surges that occur in FSH secretion during diestrus.     

The effect of pulsatile gonadotropin-releasing hormone and estradiol administration on luteinizing hormone and follicle-stimulating hormone concentrations in pituitary stalk-sectioned ovariectomized pony mares

Hourly pulses of gonadotropin-releasing hormone (GnRH) or bi-daily injections of estradiol (E2) can increase luteinizing hormone (LH) secretion in ovariectomized, anestrous pony mares. However, the site (pituitary versus hypothalamus) of positive feedback of estradiol on gonadotropin secretion has not been described in mares. Thus, one of our objectives involved investigating the feedback of estradiol on the pituitary. The second objective consisted of determining if hourly pulses of GnRH could re-establish physiological LH and FSH concentrations after pituitary stalk-section (PSS), and the third objective was to describe the declining time trends of LH and FSH secretion after PSS. During summer months, ovariectomized pony mares were divided into three groups: Group 1 (control, n = 2), Group 2 (pulsatile GnRH (25 μg/hr), n = 3), and Group 3 (estradiol (5 mg/12 hr), n = 3). All mares were stalk-sectioned and treatment begun immediately after stalk-section. Blood samples were collected every 30 min for 8 h on the day before surgery (DO) and 5 d post surgery (D5) to facilitate the comparison of gonadotropin levels before and after pituitary stalk-section. Additionally, jugular blood samples were collected every 12 hr beginning the evening of surgery, allowing for evaluation of the gonadotropin secretory time trends over the 10 d of treatment. On Day 10, animals were euthanized to confirm pituitary stalk-section and to submit tissue for messenger RNA analysis (parallel study). Plasma samples were assayed for LH and FSH by RIA. Mean LH secretion decreased from Day 0 to Day 5 in Groups 1 and 3, whereas LH secretion tended (P < 0.08) to decrease in Group 2 mares. On Day 5, LH was higher (P < 0.01) in Group 2 (17.26 ± 3.68 ng/ml; LSMEANS ± SEM), than either Group 1 (2.65 ± 4.64 ng/ml) or group 3 (4.28 ± 3.68 ng/ml). Group 1 did not differ from Group 3 on Day 5 (P < 0.40). Similarly, mean FSH levels decreased in all groups after surgery, yet Group 2 mares had significantly (P < 0.001) higher FSH concentrations (17.66 ± 1.53 ng/ml) than Group 1 or Group 3 (8.34 ± 1.84 and 7.69 ± 1. 63 ng/ml, respectively). Regression analysis of bi-daily LH and FSH levels indicated that the time trends were not parallel. These findings indicate: 1) Pituitary stalk-section lowered LH and FSH to undetectable levels within 5 d after surgery, 2) pulsatile administration of GnRH (25 μg/hr) maintained LH and FSH secretion, although concentrations tended to be lower than on Day 0, and 3) E2 did not stimulate LH or FSH secretion.     

Quantitative analysis of the effect of probenecid on pharmacokinetics of 99mTc-mercaptoacetyltriglycine in dogs

Effect of probenecid on pharmacokinetics of 99mTc-mercaptoacetylytriglycine (99mTc-MAG3) in dogs was investigated before (control), and after 15 min and 24 h of i.v. injection of probenecid (20 mg/kg). Plasma concentration-time profiles of 99mTc-MAG3 were described with a two-compartment open model. Plasma 99mTc-MAG3 clearances (Clp, ml/min/kg) were 7.9 +/- 0.5, 3.3 +/- 0.5 and 4.8 +/- 1.3 in control, 15 min and 24 h after probenecid administration respectively. Similarly, the biological half-lives at elimination phase (t(1/2), h) were 0.61 +/- 0.09, 0.79 +/- 0.11 and 0.74 +/- 0.12, and volumes of distribution at steady state (Vdss, L/kg) were 0.29 +/- 0.04, 0.20 +/- 0.05 and 0.25 +/- 0.06 respectively. The prolonged biological half-life and decreased Vdss decreased Clp significantly. Clp was a function of plasma probenecid concentration based on Michaelis-Menten kinetics. The maximum Clp inhibition (Imax) by probenecid and the plasma probenecid concentration that induced 50% of Imax (I50) were estimated to be 72 +/- 12% and 13 +/- 8 microg/ml respectively. This means that the rest (about 28%) of the Clp is not blocked by probenecid alone, suggesting the possibility of another route(s) of elimination or renal transporters which are independent from probenecid. Moreover, inter-species correlation between Clp of 99mTc-MAG3 and body weight are discussed.     

Effect of time of cisplatin administration on its toxicity and pharmacokinetics in dogs.

Cisplatin (90 mg/m2) was administered in a 5-minute bolus IV infusion to dogs at 8 AM (n = 6) or 4 PM (n = 6). Blood and urine samples were collected over a 4-hour period for statistical moment pharmacokinetic analysis. Mean urinary excretion rate of total platinum was increased, whereas mean plasma residence time of ultrafilterable platinum was decreased, in the group treated at 4 PM (PM group), compared with those treated at 8 AM (AM group). Over a 2-week postinfusion-monitoring period, both groups of dogs developed decreases in creatinine clearance, urine/serum osmolality ratio (UOsm/SOsm), specific gravity, and increase in BUN, serum creatinine concentration, urine gamma-glutamyltranspeptidase/urine creatinine ratio (UGGT/UCr), fractional excretion of magnesium, and fractional excretion of phosphate. Urine specific gravity and UOsm/SOsm were significantly decreased, whereas UGGT/UCr and BUN were significantly increased in the AM group, compared with the PM group. The time of administration had a significant effect on the pharmacokinetics of cisplatin, which resulted in significant differences in cisplatin-induced renal toxicosis.