SD Elimination Half-life Research Articles

Pharmacokinetics of furosemide administered 4 and 24 hours prior to high‐speed exercise in horses

Furosemide is a diuretic agent used commonly in racehorses to attenuate the bleeding associated with exercise-induced pulmonary hemorrhage (EIPH). The current study describes serum and urine concentrations and the pharmacokinetics of furosemide following administration at 4 and 24hrs prior to maximal exercise. Eight exercised adult Thoroughbred horses received a single IV administration of 250mg of furosemide at 4 and 24hrs prior to maximal exercise on a high-speed treadmill. Blood and urine samples were collected at time 0 and at various times for up to 72hrs and furosemide concentrations determined using liquid chromatography-tandem mass spectrometry. Serum furosemide concentrations remained above the LOQ (0.05ng/ml) for 36hrs in 3/8 and 1/8 horses in the 4- and 24-hrs groups, respectively. Serum concentration data were best fit by a two-compartment model. There was not a significant difference in the volume of distribution at steady-state (0.594±0.178 [4hrs] and 0.648±0.147 [24hrs] L/kg) or systemic clearance (0.541±0.094 [4hrs] and 0.617±0.114 [24hrs] L/hrs/kg) between horses that were exercised at 4- and 24hrs postdrug administration. The mean±SD elimination half-life was 3.12±0.387 and 3.23±0.407hrs following administration at 4 and 24hrs prior to exercise, respectively.

Pharmacokinetics of pergolide after intravenous administration to horses.

To determine the pharmacokinetics of pergolide after IV administration to horses. 8 healthy adult horses. Pergolide mesylate was administered IV at a dose of 20 μg/kg (equivalent to 15.2 μg of pergolide/kg) to each horse, and blood samples were collected over 48 hours. Pergolide concentrations in plasma were determined by means of high-performance liquid chromatography-tandem mass spectrometry, and pharmacokinetic parameters were determined on the basis of noncompartmental methods. After IV administration of pergolide, mean ± SD clearance, elimination half-life, and initial volume of distribution were 959 ± 492 mL/h/kg, 5.64 ± 2.36 hours, and 0.79 ± 0.32 L/kg, respectively. With an elimination half-life of approximately 6 hours, twice-daily dosing may be more appropriate than once-daily dosing to reduce peak-trough fluctuation in pergolide concentrations. Further pharmacodynamic and pharmacokinetic studies of pergolide and its metabolites will be necessary to determine plasma concentrations that correlate with clinical effectiveness to determine the therapeutic range for the treatment of pituitary pars intermedia dysfunction.

Pharmacokinetics, bioavailability, and hemodynamic effects of trazodone after intravenous and oral administration of a single dose to dogs

To determine the pharmacokinetics and hemodynamic effects of trazodone after IV and oral administration in dogs and bioavailability after oral administration. 6 adult Beagles. Dogs received trazodone HCl (8 mg/kg) orally and IV in a randomized controlled crossover design. Blood samples were collected at various times after administration. Heart rates and indirectly measured blood pressures of dogs and plasma concentrations and pharmacokinetics of trazodone were determined. Following IV administration, the mean ± SD elimination half-life, apparent volume of distribution, and plasma total body clearance were 169 ± 53 minutes, 2.53 ± 0.47 L/kg, and 11.15 ± 3.56 mL/min/kg, respectively. Following oral administration, the mean ± SD elimination half-life and absolute bioavailability were 166 ± 47 minutes and 84.6 ± 13.2%, respectively. Maximum plasma concentration following oral administration was 1.3 ± 0.5 μ/mL, and time to maximum plasma concentration was 445 ± 271 minutes. After IV administration, all dogs immediately developed transient tachycardia (184.3 ± 8.0 beats/min), and 3 of 6 dogs developed aggression. Increase in heart rate was significantly associated with increase in plasma drug concentration following IV administration. Results of this study indicated oral administration of trazodone resulted in acceptable absolute bioavailability, with substantial variability in time to maximum plasma concentration. Individualized approaches in dosing intervals may be necessary for dogs receiving oral trazodone. An orally administered dose of 8 mg/kg was well tolerated in dogs; IV administration of a dose of 8 mg/kg caused substantial adverse effects, including tachycardia and behavior disinhibition.

Pharmacokinetics of N-acetylcysteine after oral and intravenous administration to healthy cats

To describe the pharmacokinetics of N-acetylcysteine (NAC) in healthy cats after oral and IV administration. 6 healthy cats. In a crossover study, cats received NAC (100 mg/kg) via IV and oral routes of administration; there was a 4-week washout period between treatments. Plasma samples were obtained at 0, 5, 15, 30, and 45 minutes and 1, 2, 4, 8, 12, 24, 36, and 48 hours after administration, and NAC concentrations were quantified by use of a validated high-performance liquid chromatography-mass spectrometry protocol. Data were analyzed via compartmental and noncompartmental pharmacokinetic analysis. Pharmacokinetics for both routes of administration were best described by a 2-compartment model. Mean ± SD elimination half-life was 0.78 ± 0.16 hours and 1.34 ± 0.24 hours for the IV and oral routes of administration, respectively. Mean bioavailability of NAC after oral administration was 19.3 ± 4.4%. The pharmacokinetics of NAC for this small population of healthy cats differed from values reported for humans. Assuming there would be similar pharmacokinetics in diseased cats, dose extrapolations from human medicine may result in underdosing of NAC in cats with acute disease. Despite the low bioavailability, plasma concentrations of NAC after oral administration at 100 mg/kg may be effective in the treatment of chronic diseases.

Toxicokinetics of norditerpenoid alkaloids from low larkspur (Delphinium andersonii) orally administered to cattle

To determine the toxicokinetics of N-(methylsuccinimido)anthranoyllycoctonine-type low larkspur alkaloids in beef cattle. 5 Black Angus steers and 35 Swiss Webster mice. -Low larkspur (Delphinium andersonii) was collected, dried, ground, and administered to 5 steers via oral gavage to provide a dose of 12 mg of N-(methylsuccinimido)-anthranoyllycoctonine alkaloids/kg. Steers were housed in metabolism crates for 96 hours following larkspur administration; heart rate was monitored continuously, and blood samples were collected periodically for analysis of serum concentrations of 16-deacetylgeyerline, methyllycaconitine, geyerline, and nudicauline and assessment of kinetic parameters. The LD(50) of a total alkaloid extract from D andersonii was determined in Swiss Webster mice. -The alkaloids were quickly absorbed, with a maximum serum concentration achieved within 18 hours after administration. Geyerline and nudicauline coeluted as 1 peak and were considered together for toxicokinetic analysis. Mean ± SD elimination half-life was 18.4 ± 4.4 hours, 15.6 ± 1.5 hours, and 16.5 ± 5.1 hours for 16-deacetylgeyerline, methyllycaconitine, and geyerline and nudicauline, respectively. There were significant differences in maximum serum concentration, amount absorbed, and distribution half-life among the 4 alkaloids. The mouse LD(50) was 9.8 mg/kg. -Results suggested that clinical poisoning was likely to be most severe approximately 18 hours after exposure. Cattle should be closely monitored for at least 36 hours after initial exposure. Additionally, a withdrawal time of approximately 7 days would be required to clear > 99% of the toxic alkaloids from the serum of cattle that have ingested low larkspur.

Influence of cardiopulmonary bypass on cefuroxime plasma concentration and pharmacokinetics in patients undergoing coronary surgery

The aims of this study were to evaluate the influence of cardiopulmonary bypass (CPB) on the plasma concentrations and pharmacokinetics of cefuroxime and to assess whether the cefuroxime dose regimen (a 1.5 g dose, followed by 750 mg every 6 h for 24 h) is adequate for cardiac surgery antibiotic prophylaxis. A prospective, controlled, observational study compared patients undergoing coronary surgery with CPB (CPB group, n = 10) or off-pump surgery (off-pump group, n = 9). After each cefuroxime dose, blood samples were sequentially collected and analysed using high-efficiency chromatography. For demographic data and pharmacokinetic parameters, the authors used Fisher's exact test for nominal variables and Student's t-test and the Mann-Whitney U-test for parametric and non-parametric variables, respectively. Plasma concentrations were compared using ANOVA, and the percentage of patients with a remaining plasma concentration of >16 mg/l within 6 h after each bolus was quantified in tabular form. After each cefuroxime bolus was administered, both groups presented a significant decrease in plasma concentration over time (P < 0.001), without differences between the groups. The mean CPB time of 59.7 ± 21.1 min did not change cefuroxime plasma concentrations or pharmacokinetics. The mean clearance ± SD (ml/kg/min) and median elimination half-life (h) of the CPB group versus the off-pump group were 1.7 ± 0.7 versus 1.6 ± 0.6 (P = 0.67), respectively, and 2.2 versus 2.3 (P = 0.49), respectively. Up to 3 h following the first bolus of 1.5 g, but not after 6 h, all patients had plasma concentrations >16 mg/l (CPB group = 20% and off-pump group = 44%). However, after all 750 mg boluses were administered, concentrations <16 mg/dl were reached within 3 h. CPB does not influence cefuroxime plasma concentrations. The dosing regimen is adequate for the intraoperative period, but in the immediate postoperative period, it requires further review.

Intranasal versus Oral Administration of Lisdexamfetamine Dimesylate

Data on pharmacokinetic parameters of the prodrug stimulant lisdexamfetamine dimesylate via alternate routes of administration are limited. The pharmacokinetics of d-amphetamine derived from lisdexamfetamine dimesylate after single oral (PO) versus intranasal (IN) administration of lisdexamfetamine dimesylate were compared. In this randomized, two-period, crossover study, healthy men without a history of substance abuse were administered single PO or IN (radiolabelled with ≤100 μCi (99m)Tc-diethylenetriamine-pentaacetic acid and confirmed by scintigraphy) lisdexamfetamine dimesylate 50 mg ≥7 days apart. Serial blood samples were drawn to measure d-amphetamine and intact lisdexamfetamine at 0 (pre-dose), 15, 30 and 45 minutes and at 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 and 72 hours post-dose for PO administration and at 0 (pre-dose), 5, 10, 15, 20, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 and 72 hours post-dose for IN administration. Treatment-emergent adverse events (TEAEs) were assessed. Eighteen subjects were enrolled and completed the study. The mean ± SD maximum observed plasma concentration (C(max)) and area under the plasma concentration-time curve from time zero to time of last measurable concentration (AUC(last)) of d-amphetamine following PO administration of lisdexamfetamine dimesylate were 37.6 ± 4.54 ng/mL and 719.1 ± 157.05 ng · h/mL, respectively; after IN administration, these parameters were 35.9 ± 6.49 ng/mL and 690.5 ± 157.05 ng · h/mL, respectively. PO and IN administration demonstrated similar median time to reach C(max) (t(max)) for d-amphetamine: 5 hours for PO administration versus 4 hours for IN administration. Mean ± SD elimination half-life (t(1/2)) values were also similar for PO (11.6 ± 2.8 hours) and IN (11.3 ± 1.8 hours) lisdexamfetamine dimesylate. TEAEs after PO and IN administration were reported by 27.8% of subjects (5/18) and 38.9% of subjects (7/18), respectively; all AEs were mild or moderate in severity, and TEAEs such as anorexia, dry mouth, headache and nausea were consistent with known amphetamine effects. IN administration of lisdexamfetamine dimesylate resulted in d-amphetamine plasma concentrations and systemic exposure to d-amphetamine comparable to those seen with PO administration. Subject variability for d-amphetamine pharmacokinetic parameters was low. Both PO and IN lisdexamfetamine dimesylate demonstrated a tolerability profile similar to that of other long-acting stimulants.

Evaluation of an extractionless high-performance liquid chromatography-tandem mass spectrometry method for detection and quantitation of rosiglitazone in canine plasma

To develop a simple extractionless method for detection of rosiglitazone in canine plasma and test the method in a pharmacokinetic study after oral administration of rosiglitazone in dogs. 3 client-owned dogs with cancer. High-performance liquid chromatography-tandem mass spectrometry was performed on canine plasma. The 3 dogs with cancer in the pharmacokinetic study were assessed via physical examination and clinicopathologic evaluation and considered otherwise healthy. Food was withheld for 12 hours, and dogs were administered a single dose (4 mg/m²) of rosiglitazone. Plasma was collected at various times, processed, and analyzed for rosiglitazone. The developed method was robust and detected a minimum of 0.3 ng of rosiglitazone/mL. Mean ± SD maximum plasma concentration was 205.2 ± 79.1 ng/mL, which occurred at 3 ± 1 hours, and mean ± SD elimination half-life was 1.4 ± 0.4 hours. The area under the plasma rosiglitazone concentration-versus-time curve varied widely among the 3 dogs (mean ± SD, 652.2 ± 351.3 ng/h/mL). A simple extractionless method for detection of rosiglitazone in canine plasma was developed and was validated with excellent sensitivity, accuracy, precision, and recovery. The method enabled unambiguous evaluation and quantitation of rosiglitazone in canine plasma. This method will be useful for pharmacokinetic, bioavailability, or drug-drug interaction studies. Oral rosiglitazone administration was well tolerated in the dogs.

Pharmacokinetics and bioavailability of cefquinome in healthy ducks

To determine pharmacokinetics and bioavailability of cefquinome administered IV, IM, or PO to healthy ducks. Thirty-six 2-month-old Muscovy ducks. Ducks were randomly assigned to 3 groups of 12 birds each for a single IV, IM, or PO administration at a dose of 5 mg/kg. Blood samples were collected before and at various intervals after each administration. Cefquinome concentration was determined by use of high-performance liquid chromatography at 268 nm with a UV detector, and pharmacokinetics were analyzed. The disposition of cefquinome following IV or IM administration was best described by a 2-compartment model. After IV administration, mean ± SD elimination halflife was 1.57 ± 0.06 hours, clearance value was 0.22 ± 0.02 L/kg·h, and apparent volume of distribution at steady state was 0.41 ± 0.04 L/kg. After IM administration, elimination half-life was 1.79 ± 0.13 hours, peak concentration time was 0.38 ± 0.06 hours, peak drug concentration was 9.38 ± 1.61 μg/mL, and absolute mean ± SD bioavailability was 93.28 ± 13.89%. No cefquinome was detected in plasma after PO administration. Results indicated that cefquinome was absorbed quickly and had excellent bioavailability after IM administration, but absorption after PO administration was poor.

Pharmacokinetics of metformin after enteral administration in insulin-resistant ponies

To determine pharmacokinetics and plasma steady-state kinetics of metformin after oral or nasogastric administration in insulin-resistant (IR) ponies. 8 IR ponies. Metformin (30 mg/kg) was administered to 8 ponies via nasogastric tube Blood samples were collected at intervals for 24 hours. Plasma concentrations of metformin were measured via liquid chromatography-electrospray tandem mass spectroscopy Pharmacokinetic variables were determined via noncompartmental analysis. Metformin (15 mg/kg, PO, twice daily [8 am and 5 pm]) was administered to 4 ponies for an additional 20 days, and blood samples were obtained every 2 days. Plasma concentration at steady state (Css) was determined. Mean±SD elimination half-life (t1/2) of metformin was 11.7±5.2 hours, maxima plasma concentration was 748±269 ng/mL at 54±32 minutes, mean area under the curve was 355±92 microg.h/mL, and apparent clearance was 90.6±28.1 mL/min/kg. The Css was 122±22 ng/mL. Metformin reportedly enhances insulin sensitivity of peripheral tissues without stimulating insulin secretion, but bioavailability in horses is low. The t1/2 of metformin in IR ponies was similar to that in humans. Actual clearance of metformin adjusted for bioavailability in IR ponies was similar to that in humans; however, during chronic oral administration at dosages reported in efficacy studies, the Css of metformin was less than values associated with therapeutic efficacy in humans The apparent lack of long-term efficacy of metformin in horses is likely attributable to low bioavailability, rather than to rapid clearance.

Pharmacokinetics and tissue distribution of minocycline hydrochloride in horses

To determine the pharmacokinetics and tissue distribution of minocycline in horses. 5 healthy Thoroughbred mares for the pharmacokinetic experiment and 6 healthy Thoroughbred mares for the tissue distribution experiment. Each mare was given 2.2 mg of minocycline hydrochloride/kg, IV. Blood samples were collected once before minocycline administration (0 hours) and 10 times within 48 hours after administration in the pharmacokinetics study, and 24 tissue samples were obtained at 0.5 and 3 hours in the distribution study. No adverse effects were observed in any of the mares after minocycline administration. The mean+/-SD elimination half-life was 7.70+/-1.91 hours. The total body clearance was 0.16+/-0.04 L/h/kg, and the volume of distribution at steady state was 1.53+/-0.09 L/kg. The percentage of plasma protein binding was 68.1+/-2.6%. Plasma concentration of free minocycline was 0.12 microg/mL at 12 hours. Minocycline was not detected in brain tissue, CSF or aqueous humor at 0.5 hours; however, it was found in all tissues, except in the aqueous humor, at 3 hours. Clearance of minocycline in healthy mares was greater than that reported for humans. For effective treatment of infections with common equine pathogens, it will be necessary to administer minocycline at a dosage of 2.2 mg/kg, IV, every 12 hours. This drug could be useful for infections in many tissues, including the CNS. The pharmacokinetic and tissue distribution data should aid in the appropriate use of minocycline in horses.

Pharmacokinetics and Pharmacodynamics of 15-Deoxyspergualin in a Canine Renal Allograft Model of Local Immunosuppression

Local immunosuppression is based on the rationale that one can simultaneously prevent rejection and reduce systemic side effects by administering appropriately chosen immunosuppressive agents directly into the allograft. We utilized a mongrel canine renal transplant model with a programmable, implantable pump/catheter system to estimate the first-pass extraction of 15-deoxyspergualin (DSG) during renal artery infusion and to compare the efficacy and toxicity of continuous intraarterial (ia) versus intravenous (iv) DSG delivery. Six autotransplanted dogs were given DSG by both iv bolus (1 mg/kg) and ia infusion (1.0 mg/kg/d). DSG was administered to allograft recipients by continuous ia infusion at 0.5 (n= 11) and 0.75 (n= 8) mg/kg/day and by continuous iv infusion at 0.5 (n= 12) and 0.75 (n= 6) mg/kg/day. Mean ± SD elimination half-life was 0.6 ± 0.1 hr, and the transplanted kidney removed as much as 55–88% (mean 66%) of locally infused DSG. When compared with untreated controls [mean survival time (MST) = 8 days], low-dose (0.5 mg/kg/day) DSG produced a significant antirejection effect when given ia (MST = 12 days;P= 0.04) but not iv (MST = 9 days;P= 0.09), with equivalent overall mean drug levels during normal renal function. However, two of the four longest-surviving animals in the ia group died from severe systemic toxicity, manifested by anorexia, diarrhea, leukopenia, and sepsis. High-dose (0.75 mg/kg/day) DSG significantly prolonged survival via both local (MST = 12 days;P= 0.04) and systemic (MST = 11 days;P= 0.02) routes, but half of the iv-treated dogs died from, and four of the longer-surviving ia-treated animals manifested signs of, systemic toxicity, with significantly higher mean drug levels in the iv group. DSG significantly suppressed vascular rejection at both doses when administered locally and systemically, dose-dependently affected the severity of tubulointerstitial rejection and graft edema, and was not nephrotoxic. Our autotransplant pharmacokinetic data overestimated the allografted kidney's ability to extract DSG during local infusion of slightly lower, but immunosuppressive, doses, so that death from systemic toxicity was not prevented and a direct survival benefit of ia vs iv therapy was not realized. Local DSG administration might be combined with other immunosuppressants to therapeutic advantage.

Haemodynamics, cardiac conduction and pharmacokinetics of mibefradil (Ro 40???5967), a novel calcium antagonist

Mibefradil (Ro40-5967) is a chemically novel non-dihydropyridine calcium antagonist. In this phase II study we compared its acute and chronic effects on blood pressure, heart rate and atrioventricular conduction (electrocardiographic PQ interval) with those of verapamil and diltiazem. After a 4-week placebo run-in, 18 patients with mild to moderate essential hypertension were given single doses of mibefradil (150 mg), slow-release (SR) verapamil (240 mg), diltiazem (240 mg) and placebo at weekly intervals; pharmacokinetics and the effects on blood pressure, heart rate and PQ interval were studied on four 10-h study days. Seventeen of the same patients subsequently underwent 4 weeks of treatment with either mibefradil (100 mg daily; n = 10) or verapamil SR (240 mg daily; n = 7), and on the last day, they attended a further 10-h study day. Two studies were conducted: an acute, single-dose, double-blind, randomly allocated, placebo-controlled, crossover study and a chronic, open-label, randomly allocated, parallel-group study. Mibefradil was well tolerated. In the acute study, the antihypertensive effect (difference from placebo) of mibefradil 150 mg was of slower onset than that of verapamil or diltiazem, but comparable blood pressure reductions had been achieved by 6 h. The mean +/- SD maximal PQ prolongation (difference from placebo) was 15.6 +/- 16.1 ms, compared with 44.0 +/- 22.6 ms for verapamil and 56.0 +/- 48.9 ms for diltiazem (P<0.05 mibefradil versus verapamil; P<0.01 mibefradil versus diltiazem). In the chronic study there were no significant differences during steady-state conditions between mibefradil at 100 mg and verapamil SR at 240 mg in their effects on blood pressure, PQ and heart rate. The mean +/- SD elimination half-life (t1/2) of mibefradil under steady-state conditions was 26.8 +/- 5.5 h (versus an apparent t1/2 of 16.9 +/- 11.1 h for verapamil SR, P<0.05). Mibefradil is a well-tolerated and efficacious antihypertensive agent well suited to single daily dosing because of its intrinsic long plasma half-life. The effects on both blood pressure and PQ interval are of more gradual onset than those of unmodified verapamil and diltiazem after single doses.

The Pharmacokinetics of a Single Dose of Artemisinin in Healthy Vietnamese Subjects

The pharmacokinetics of artemisinin was studied in 12 healthy male Vietnamese subjects after a single, 500-mg, oral dose. A total of 14 plasma samples per subject was obtained up to 48 hr after drug intake. Measurement of artemisinin concentration was performed by high-performance liquid chromatography with electrochemical detection. Tolerance was evaluated by recording subjective and objective findings including repeated physical examination, routine blood investigation, and electrocardiograms. Fitting of the concentration-time curve and pharmacokinetic calculations revealed the following results: a mean +/- SD volume of distribution/dose ratio of 19.4 +/- 6.9 L/kg, a mean +/- SD absorption half-life of 0.58 +/- 0.54 hr with a mean +/- SD calculated maximum concentration of 391 +/- 147 micrograms/L occurring at 1.81 +/- 0.73 hr after drug intake. Elimination was rapid, with a mean +/- SD elimination half-life of 2.59 +/- 0.55 hr. Peak concentrations were sufficient with regard to antimalarial activity although bioavailability appears to be very low. The relatively small interindividual variation in pharmacokinetics does not seem to be of clinical significance. Tolerance to the single dose of artemisinin was good: no adverse effects were detected. Based on these results, a treatment schedule of 2 x 500 mg of artemisinin (oral dose) per day can be advised. This will result in adequate antimalarial plasma concentrations, despite poor bioavailability, and rapid elimination.

Single-dose and steady-state pharmacokinetics and pharmacodynamics of oxycodone in patients with cancer.

The single-dose and steady-state pharmacokinetics and pharmacodynamics of oxycodone have been determined in patients with moderate to severe cancer pain. The mean +/- SD elimination half-life after single-dose administration of intravenous (4.6 mg to 9.1 mg) and oral (9.1 mg) oxycodone was 3.01 +/- 1.37 hours and 3.51 +/- 1.43 hours, respectively. After intravenous administration, the mean +/- SD volume of distribution was 211.9 +/- 186.6 L, and the mean +/- SD total plasma clearance was 48.6 +/- 26.5 L/hr. The mean absolute oral bioavailability of oxycodone was 87%, and the mean +/- SD volume of distribution after oral administration was 249.1 +/- 204.3 L. When administered orally as 10 mg oxycodone hydrochloride every 4 hours, there was no accumulation of oxycodone at steady state and the mean +/- SD steady-state concentration was 34.6 +/- 10.3 micrograms/L. Intravenous oxycodone produced a faster onset of pain relief than oxycodone tablets, but the duration of analgesia was approximately the same (4 hours). However, the incidence of side effects and their severity were significantly higher (p < 0.05) for intravenous oxycodone than for oxycodone tablets. The marked interindividual variation observed in the pharmacokinetics and pharmacodynamics of oxycodone in this study supports the need for individualized dosing regimens.

MIZORIBINE PHARMACOKINETICS AND PHARMACODYNAMICS IN A CANINE RENAL ALLOGRAFT MODEL OF LOCAL IMMUNOSUPPRESSION1,2

We utilized a canine renal transplant model to estimate the first-pass extraction of mizoribine (MZB) during renal artery infusion and to compare the efficacy and toxicity of continuous intraarterial (i.a.) versus intravenous (i.v.) MZB delivery, with and without a background of oral cyclosporine. Five autotransplanted mongrel dogs with programmable, implantable pump/catheter systems were given MZB by both i.v. bolus (5 mg/kg) and i.a. infusion (5.0 mg/kg/day). Mean +/- SD elimination half-life was 3.02 +/- 0.81 hr, and the transplanted kidney removed as much as 47-59% (mean 56%) of locally infused MZB. With increasing local and systemic MZB delivery in a single autografted dog undergoing both i.a. and i.v. pump/catheter placement, renal extraction decreased from at least 47% (5.0 mg/kg/day) to 33% (7.5 mg/kg/day), finally to 18% (10.0 mg/kg/day). A dose of 3.0 mg/kg/day MZB did not significantly prolong survival of renal allograft recipients over that of untreated controls (median survival time [MST] = 8 days) when administered either locally (MST = 9 days) or systemically (MST = 12 days). All dogs receiving 4.0 mg/kg/day MZB i.a. died from rejection, and a survival advantage was still not realized (MST = 7 days). In contrast, 4.0 mg/kg/day i.v. prolonged survival over controls (MST = 14 days; P = 0.03) but not when directly compared with the i.a. group (P = 0.30), and produced death from severe debility in five of seven animals with significantly higher mean systemic MZB levels (P = 0.02). Four of six dogs receiving 5.0 mg/kg/day MZB i.a. (MST = 14 days) and two of four dogs receiving 5.0 mg/kg/day i.v. (MST = 14 days) died from severe debility, though survival in both groups was prolonged over control values (P = 0.01 and P = 0.05, respectively). Coadministration of a subtherapeutic dose of oral CsA (5 mg/kg/day) significantly prolonged the overall survival of dogs receiving MZB 4.0 mg/kg/day i.a. (MST = 23; P = 0.01) but not i.v. (MST = 11; P = 1.00), so that a significant difference in overall survival between the combined MZB i.a. + CSA and MZB i.v. + CSA groups was now realized in favor of the former (P = 0.04). We conclude that at local doses required to achieve immunosuppression, the transplanted kidney was not able to extract enough MZB to prevent death from systemic toxicity, presumably as a result of saturation of renal elimination mechanisms, so that an overall survival benefit was not realized.(ABSTRACT TRUNCATED AT 400 WORDS)