Reconstruction of wave front and object for inline holography from a set of detection planes.

We illustrate the errors inherent in the conventional empty beam correction of full field X-ray propagation imaging, i.e. the division of intensities in the detection plane measured with an object in the beam by the intensity pattern measured without the object, i.e. the empty beam intensity pattern. The error of this conventional approximation is controlled by the ratio of the source size to the smallest feature in the object, as is shown by numerical simulation. In a second step, we investigate how to overcome the flawed empty beam division by simultaneous reconstruction of the probing wavefront (probe) and of the object, based on measurements in several detection planes (multi-projection approach). The algorithmic scheme is demonstrated numerically and experimentally, using the defocus wavefront of the hard X-ray nanoprobe setup at the European Synchrotron Radiation Facility (ESRF).

Disposition of oral azithromycin in humans.

BACKGROUND: The oral bioavailability of azithromycin is approximately 37% in healthy subjects; little is known about the disposition of the remaining 63% of the dose. This study attempted to describe the fate of azithromycin before absorption. METHODS: Twelve subjects with ileostomies in place for > 1 month were studied in this open-label, randomized, three-center, two-period, two-treatment crossover study. Subjects randomly received single 500 mg intravenous infusion (over 1 hour) or two 250 mg oral capsules after a fast for > 12 hours. Blood and ileostomy samples were collected serially after each administration and analyzed for azithromycin and two metabolites (descladinose and 9a-N-desmethyl metabolites) by HPLC with electrochemical detection. RESULTS: Mean +/- SD peak concentration values after oral and intravenous administration were 0.21 +/- 0.08 and 3.40 +/- 1.12 microgram/ml. Mean values for area under the serum concentration versus time curve were 1.27 +/- 0.65 and 7.14 +/- 1.34 micrograms x hr/ml, respectively. The absolute bioavailability of 16.2% was approximately one-half the value observed previously in healthy subjects. Recovery in ileostomy fluid (percent of dose in 24 hours) or azithromycin, descladinose, and 9a-N-desmethyl metabolites were 13%, 0.5%, and 1% (total, 15%) after intravenous dosing and 47%, 13%, and 2% (total, 62%) after oral dosing. Total and ileal clearances were 776 +/- 126 and 158 +/- 63 ml/min after intravenous dosing. CONCLUSION: Because more descladinose metabolite was detected after oral dosing, acid degradation of azithromycin before absorption contributed to some loss in oral bioavailability. Further, ileal clearance (biliary plus intestinal excretion clearance) in this population represented 21% of total clearance. Taken together, these data suggest that the cause of low oral bioavailability of azithromycin is the result of incomplete absorption rather than acid degradation or extensive first-pass metabolism.

Validity of creatinine clearance estimates in the assessment of renal function.

In clinical practice, estimations of renal function are commonly used to calculate the appropriate dose for drugs that are renally cleared. Continuous-infusion inulin clearance (CLIN), 4-hour creatinine clearance (CLCR,m), and 24-hour creatinine clearance (CLCR,a) were measured in 109 subjects (86 men and 23 women) with varying degrees of stable renal function (CLIN, 6 to 209 ml/min) and compared with CLCR values as predicted by five equations on the basis of plasma creatinine concentrations, age, weight, and/or height. The CLCR,m was positively correlated with CLIN (r = 0.92; p less than 0.0001) but exceeded CLIN by 15% between the range of 30 and 209 ml/min (CLIN). Similarly, CLCR,a correlated well with both CLCR,m (r = 0.84; p less than 0.0005) and CLIN (r = 0.84; p less than 0.0001). The relative role of tubular secretion in the overall clearance of creatinine increased with declining CLIN and exceeded 40% when CLIN was below 30 ml/min. CLCR estimated by the Cockcroft-Gault and Mawer methods did not significantly differ from either CLCR,m or CLCR,m, whereas the other equations generally underestimated CLCR. Among the numerous mathematical equations, CLCR as estimated by the method proposed either by Mawer or Cockcroft and Gault was the best predictor of CLIN (CLIN = 1.05CLRCR - 18.38 or CLIN = 1.12CLCR - 20.60, respectively; r = 0.81; p less than 0.0001). The present data support the use of estimator equations proposed by Cockcroft and Gault or Mawer for rapid estimation of renal function in the clinical setting.

The disposition and dynamics of labetalol in patients on dialysis.

The disposition of labetalol was assessed in 16 patients on dialysis after intravenous dosing with 0.7 to 1.0 mg/kg during an interdialytic period and just before hemodialysis (n = 8) and during continuous ambulatory peritoneal dialysis (CAPD) (n = 8). The plasma concentration time data exhibited triexponential decay in all patients. The terminal t 1/2 of labetalol was 12.90 +/- 4.68 hours, the total body clearance was 1198.2 +/- 249.4 ml/min, and the AUC was 921.4 +/- 175.2 ng hr/ml during the interdialytic period. No significant changes were observed in these parameters after dosing with labetalol just before dialysis. The hemodialysis clearance of labetalol was 30.67 +/- 5.49 ml/min, and only 0.189 +/- 0.042 mg of labetalol was removed by hemodialysis. The terminal t 1/2 averaged 13.05 +/- 6.32 hours during CAPD. Steady-state volume of distribution, total body clearance (Clp), and CAPD clearance were 10.39 +/- 2.77 L/kg, 1397.2 +/- 372.3 ml/min, and 1.94 +/- 0.65 ml/min, respectively. The fraction of the dose recovered in the CAPD dialysate during the 72-hour study period was 0.14% +/- 0.09%. The decay of the antihypertensive effect of labetalol was gradual and paralleled the decline in the log plasma concentration. There was a significant correlation between labetalol plasma concentration and the fall in supine diastolic and mean blood pressure after the interdialytic dose and during CAPD. Although labetalol is removed by dialysis, dialysis does not significantly enhance Clp.

Pentoxifylline in the isolated perfused rat kidney.

The effects of pentoxifylline, a new methylxanthine with marked hemorrheologic properties, were studied following brief renal artery occlusion in the isolated rat kidney model perfused with cell-free Krebs-Henseleit buffer. Anuria was observed in 3 of 6 control kidneys within 5 min after reperfusion; urine flow was maintained in all rat kidneys perfused with pentoxifylline (2500 ng/ml). Glomerular filtration rate was significantly greater in kidneys administered pentoxifylline compared with controls following 40 min of postocclusion reperfusion (460 +/- 100 vs. 100 +/- 110 microliters/min/gKW; P less than 0.01). Pretreatment of kidneys with indomethacin, a nonspecific cyclooxygenase inhibitor, blocked the protective effects of pentoxifylline in this setting. These data suggest that the addition of pentoxifylline may prevent hypoxia-related changes in renal function of transplanted kidneys. Stimulation of renal prostaglandin synthesis, as well as an interaction at the level of the adenosine receptors, were most likely responsible for the observed beneficial effects of pentoxifylline.

Evaluation of amphotericin B-cyclosporine interaction in the rat.

Although a significant interaction between cyclosporine and amphotericin-B (AmpB) has been observed clinically, these findings have not been duplicated in animal studies. A total of 64 male albino rats were used in single- and multiple-dose experiments with AmpB and CsA in the absence or presence of systemic Candida infection. No significant differences in glomerular filtration rate were found in rats given single i.v. doses of AmpB 1 mg/kg compared with AmpB and CsA. Furthermore, rats given i.p. AmpB 1 mg/kg and CsA 10 mg/kg daily for 10 days showed no significant differences in GFR compared with animals given CsA alone. Morphology and CsA whole-blood pharmacokinetics were not different between groups administered single-dose CsA, AmpB, or the combination; similarities also existed with multiple-dose studies. In an attempt to mimic the clinical setting, 2 groups of rats were administered i.p. CsA 10 mg/kg/day for 10 days followed by inoculation of Candida albicans. After 48 hr, a single i.v. dose of AmpB 1.0 mg/kg was associated with a 33% decline in GFR compared with those given sterile water (P less than 0.05). Systemic clearance of CsA was markedly reduced in candidiasis rats administered AmpB compared with controls given sterile water. A significant reduction in renal Candida colony-forming units was found in rats given CsA and AmpB compared with those administered CsA alone. These data suggest that the presence of systemic Candida highlights the interaction of CsA and AmpB in the rat model.

Effects of cyclosporine on the isolated perfused rat kidney.

Although cyclosporine (CsA) has been shown to cause decreased renal function in humans, the mechanisms important in cyclosporine nephrotoxicity are not well understood. Investigations of cyclosporine nephrotoxicity in animal models have been complicated by systemic toxic effects not seen in humans. In the present study, the direct renal effects of cyclosporine were investigated in the isolated perfused rat kidney (IPRK) model. Cyclosporine delivered by nontoxic liposomes had no effect on IPRK resistance, perfusate flow, inulin clearance, or fractional reabsorption of sodium, despite marked tissue accumulation of CsA (55.1 +/- 7.2 micrograms/g kidney tissue). In contrast, a 63% decrease in inulin clearance was observed following the administration of intravenous cyclosporine (0.1 ml). However, similar changes in IPRK function were seen after the administration of 0.1 ml of the intravenous cyclosporine vehicle, cremophor, suggesting that the alterations in function were secondary to the vehicle. All together, these findings suggest that cyclosporine nephrotoxicity may be secondary to renal innervation, toxic metabolites, or other systemic effects of cyclosporine not present in the IPRK.

Methylprednisolone, cyclosporine and methotrexate for prophylaxis of acute graft-versus-host disease.

Twenty-four patients were given the combination of methylprednisolone 100 mg i.v. on day 0, cyclosporine 2 mg/kg i.v. every 12 h starting on day -3 and methotrexate 5 mg/m2 on days 1, 3, and 6, then 10 mg/m2 on days 11 and 18 after allogeneic bone marrow transplantation for hematological malignancies for the prophylaxis of acute graft-versus-host disease. (GVHD). Methylprednisolone was given prior to the marrow infusion for its lympholytic effect. The methotrexate dose on days 1, 3, and 6 was half of that given in other studies to decrease the early toxicities. The outcome of this group is compared with patients transplanted before 1988 and given methotrexate alone, methotrexate with prednisone, or cyclosporine alone. There is no difference in relapse and survival between the groups at this time. The rate of engraftment and incidence of mucositis with the combination is not significantly different from the cyclosporine group. No patient developed greater than grade II acute GVHD with the combination. The probability of grade II or higher acute GVHD with the combination (14%) is significantly less than methotrexate, with or without prednisone or cyclosporine alone.

Longitudinal study of cyclosporine and lipids in patients undergoing bone marrow transplantation.

The metabolic effects of intravenous cyclosporine on lipids and lipoproteins were studied in 29 allogeneic bone marrow recipients compared with 13 autologous bone marrow patients not requiring cyclosporine therapy. Patients were monitored continuously from 5 days prior to 27 days following transplantation; cyclosporine treatment was initiated 4 days before transplantation. Fasting lipid and lipoprotein levels were measured in serial blood samples throughout the study period. Nutritional supplementation, conditioning regimens and concomitant medications were not significantly different between groups. Furthermore, no significant differences in age, weight, lipid, or lipoprotein levels were found at baseline between the patient groups. Cholesterol, triglyceride, low-density lipoprotein cholesterol, and very low-density lipoprotein cholesterol levels remained unchanged in autologous patients. As compared with baseline values, plasma total cholesterol increased by an average of 26 percent in allogeneic transplantation patients receiving cyclosporine. Similarly, the ratio of low-density lipoprotein to high-density lipoprotein cholesterol was fourfold greater in those patients treated with cyclosporine compared to the autologous group. We conclude that cyclosporine appears to elevate cholesterol levels. Neither acute graft vs host disease nor changes in hepatic function could explain the differences in plasma cholesterol levels between groups.

Influence of human serum albumin content in formulations on the bioequivalency of interferon alfa-2a given by subcutaneous injection in healthy male volunteers.

To determine the influence of human serum albumin (HSA) content in formulations on the bioequivalency of recombinant interferon alfa-2a, a double-blind, randomized, two-way crossover study was conducted in 24 healthy male volunteers. Subjects received a single subcutaneous injection of 18 million IU of Roferon-A reconstituted with either the diluent containing 10 mg of HSA or the HSA-free diluent; final HSA contents in the 2 formulations were 15 mg and 5 mg, respectively. Administration of the 2 formulations resulted in similar 48-hour Roferon-A serum concentration-time profiles and comparable frequency and intensity of adverse events. The statistical analysis using the two one-sided tests procedure showed that both formulations were bioequivalent for pharmacokinetic parameters such as Cmax, tmax, AUC48, and AUC. We conclude that a threefold change in HSA content in formulations does not alter the bioequivalency of Roferon-A.

Acute hepatotoxicity after excessively high doses of carbamazepine on two occasions.

A 2 1/2-year-old child being treated with carbamazepine (CBZ) for a seizure disorder on two separate occasions experienced elevated CBZ serum concentrations (28 and 23.2 mg/L), severe liver damage (SGOT greater than 6000 IU, SGPT greater than 5000 IU), and central nervous system manifestations (coma, lethargy, seizures). During the first episode, the time course of CBZ concentrations exhibited a nonlinear decline and was accompanied by CBZ-10,11-epoxide concentrations that were elevated 4-fold compared to normal values. Cerebrospinal fluid concentrations of CBZ and CBZ-10,11-epoxide were also elevated, although their ratios to serum concentrations did not suggest enhanced permeability of the central nervous system to these substances. The concentrations of CBZ-10,11-epoxide but not CBZ were elevated for the duration of time that the patient was comatose, suggesting that this metabolite may contribute to the neurotoxic side effects observed with CBZ therapy.

Therapeutic drug monitoring of cyclosporine-lipoprotein levels.

Cyclosporine therapy is complicated by nephrotoxicity that is not predicted by drug levels. In this study serial trough blood samples were obtained from 11 allogeneic marrow transplant recipients after initiation of intravenous cyclosporine 2 mg/kg every 12 hours for a period extending 4 weeks after transplantation. Renal dysfunction, assessed by an increase in serum creatinine levels to twice baseline values or when greater than 175 mumol/L, was found in four patients. No associations between renal dysfunction and cyclosporine levels in whole blood, total plasma, or lipoprotein fractions were found. The ratios of maximum and mean high-density low-density lipoprotein cyclosporine concentrations were greatest in patients with renal dysfunction (p less than 0.001). The data suggest therapeutic drug monitoring of cyclosporine in various biologic fluids does not predict onset of drug-associated renal dysfunction. However, the relative role of high-density to low-density lipoprotein transport of cyclosporine may provide an index of renal functional changes associated with the agent.

Pharmacokinetics of azithromycin after single- and multiple-doses in children.

STUDY OBJECTIVE: To characterize the disposition and tolerance of azithromycin after single and multiple oral doses of 12 mg/kg in children with and without cancer. DESIGN: Open-label, nonrandomized pharmacokinetic study. SETTING: Two pediatric hospitals. PATIENTS: Twelve children with cancer admitted to the inpatient unit for empiric antibiotic treatment of febrile neutropenia, and 16 hospitalized patients receiving antibiotic therapy INTERVENTIONS: Patients received azithromycin suspension either as a single dose or daily dose every morning for 5 consecutive days. Serial blood samples were collected up to 120 hours after a single dose or during and after multiple doses to characterize the pharmacokinetic parameters estimated for a two-compartment absorption model. MEASUREMENTS AND MAIN RESULTS: All 28 patients were evaluable for safety. Azithromycin was well tolerated except in one patient with cancer who experienced abdominal cramps and withdrew from the study. Pharmacokinetic results were not determined in five patients because of insufficient concentration-time data. The mean +/- SD estimates of oral clearance, terminal half-life, maximum concentration in serum (Cmax), and time to achieve Cmax in the 23 evaluable patients were 4.83 +/- 3.59 L/hour/kg, 54.5 +/- 36.4 hours, 318.2 +/- 174.5 microg/L, and 2.4 +/- 1.1 hours, respectively. These estimates did not differ between single-dose (14 patients) and multiple-dose (9 patients) groups. Pharmacokinetic parameters were not different between the 11 children with cancer and the 12 without cancer. CONCLUSION: Azithromycin 12 mg/kg results in proportionately higher serum concentrations than previously published results for lower doses (5 mg/kg). Variability in concentration profiles among patients is substantial, and age or other yet unidentified clinical factors may explain some of the differences observed.

Treatment of acute gynecologic infections with trovafloxacin. Trovafloxacin Surgical Group.

BACKGROUND: Trovafloxacin, a broad-spectrum fourth-generation quinolone with gram-positive and gram-negative aerobic and anaerobic bacterial activity, is available in oral and intravenous formulations. The objective of this prospective, multicenter, double-blind, randomized study was to compare the efficacy of trovafloxacin with that of cefoxitin, an approved drug for treatment of acute gynecologic infections, together with amoxicillin/clavulanic acid as oral follow-on treatment. METHODS: Patients with a clinical diagnosis of acute pelvic infection received either intravenous alatrofloxacin with oral trovafloxacin follow-on (trovafloxacin) or a combined regimen of cefoxitin followed by amoxicillin/clavulanic acid for a maximum of 14 days. The primary endpoint was clinical response to therapy on follow-up at day 30. RESULTS: Clinical success rates were comparable between the trovafloxacin (n = 107) and comparative (n = 119) groups at study end (90% vs. 86%, respectively; 95% confidence interval, -4.5, 12.5). Among clinically evaluable patients, clinical success rates for infections involving Enterococcus species were higher with trovafloxacin than with the comparative regimen at the end of treatment (96% and 85%) and at study end (96% and 86%). CONCLUSION: Intravenous alatrofloxacin followed by oral trovafloxacin for a maximum of 14 days of total therapy was efficacious in the treatment of acute pelvic infections.

Double-blind comparison of single-dose alatrofloxacin and cefotetan as prophylaxis of infection following elective colorectal surgery. Trovafloxacin Surgical Group.

BACKGROUND: Alatrofloxacin, the prodrug of trovafloxacin, is a novel fluoroquinolone antimicrobial agent with a broad spectrum, including activity against gram-positive and gram-negative aerobes and anaerobes. Its pharmacokinetic properties (long half-life, excellent tissue distribution, and good safety profile) suggest a role in surgical prophylaxis. This prospective, multicenter, double-blind trial compared alatrofloxacin with cefotetan, an approved drug for surgical prophylaxis, in reducing postoperative infections. METHODS: The efficacy and safety of a single 200-mg intravenous dose of alatrofloxacin were compared to a single 2-g intravenous dose of cefotetan in 492 patients undergoing elective colorectal surgery. The efficacy of alatrofloxacin as a prophylaxis for wound, intra-abdominal, or remote-site postoperative infectious complications was compared with cefotetan in 317 clinically evaluable patients; 161 received alatrofloxacin and 156 received cefotetan. The patients were monitored for infections and safety for 30 days postoperatively. RESULTS: No statistically significant between-treatment difference was detected in successful clinical response rates at the end of the study (72% for each group). The incidence of primary wound infections at the time of hospital discharge was also similar: 21% in patients treated with alatrofloxacin and 18% in those treated with cefotetan. Safety, established by the incidence of adverse events, did not differ statistically between the groups. CONCLUSIONS: A single intravenous dose of alatrofloxacin given within 4 hours prior to surgery was as effective as an intravenous dose of cefotetan in the prevention of postoperative infectious complications in patients undergoing elective colorectal surgery. The safety profiles of the two medications were similar.

Trovafloxacin in the treatment of intra-abdominal infections: results of a double-blind, multicenter comparison with imipenem/cilastatin. Trovafloxacin Surgical Group.

BACKGROUND: Trovafloxacin, a new broad-spectrum fourth-generation quinolone, has in vitro activity against most gram-negative and gram-positive anaerobes and aerobes. Trovafloxacin is available as both an intravenous formulation, alatrofloxacin, and a single daily oral tablet. Excellent tissue pharmacokinetics and oral bioavailability suggest usefulness in the treatment of complicated intra-abdominal infections. Thus, the efficacy of alatrofloxacin followed by oral trovafloxacin was compared with the standard regimen of intravenous imipenem/cilastatin followed by oral amoxicillin/clavulanic acid in this prospective, multicenter, double-blind trial. METHODS: Patients were randomized to receive either 300 mg alatrofloxacin daily followed by 200 mg oral trovafloxacin daily or 1 g imipenem/cilastatin intravenously thrice daily followed by 500 mg oral amoxicillin/clavulanic acid thrice daily for up to 14 days following surgical intervention of a documented intra-abdominal infection. Efficacy was assessed at the end of therapy and at follow-up (day 30). RESULTS: At the end of the study, cure or improvement occurred in 83% (129/156) and 84% (127/152) of clinically evaluable patients in the trovafloxacin and comparative groups, respectively. Pathogen eradication rates, adverse-event profiles, and significant laboratory abnormalities were comparable between groups. CONCLUSION: Intravenous alatrofloxacin with or without oral trovafloxacin was as effective as intravenous imipenem/cilastatin followed by oral amoxicillin/clavulanic acid in complicated intra-abdominal infections.

Inhibition of pentoxifylline clearance by cimetidine.

The effect of cimetidine on the single-dose pharmacokinetics of pentoxifylline and one of its major metabolites, 3,7-dimethyl-1-(5-hydroxyhexyl)xanthine (1), was examined in two groups of male Sprague-Dawley rats (6 rats/group) after the administration of pentoxifylline (1 mg/kg) alone and following a 50 mg/kg iv dose of cimetidine. The addition of cimetidine resulted in a 37% decrease in pentoxifylline clearance (23.8 +/- 7.5 versus 15.0 +/- 3.2 mL/min; p less than 0.03). No changes in the volume of distribution of pentoxifylline or in the total area under the plasma concentration-time curve for 1 were observed with the addition of cimetidine. The mechanism of this metabolic interaction is probably cimetidine-induced inhibition of hepatic microsomal enzymes, which blocks the major excretory pathways for pentoxifylline. Further studies are warranted in humans to determine the existence and clinical significance of this interaction.

Pharmacokinetics of cyclosporine in bone marrow transplantation: longitudinal characterization of drug in lipoprotein fractions.

The pharmacokinetics of cyclosporine (CSA; 2 mg/kg given iv over a period of 2 h every 12 h) in whole blood, plasma, high-density lipoproteins (HDL), and low-density lipoproteins (LDL) were studied after single (n = 10) and multiple (31 days; n = 6) doses in patients receiving allogeneic bone marrow transplants. Whereas HDL-cholesterol levels decreased significantly, LDL-cholesterol levels increased from day 1 to day 31 of CSA dosing. The mean area under the concentration-time curve and half-life values of CSA in whole blood or total plasma did not differ after single or multiple doses. Greater amounts of CSA were contained in the HDL relative to the LDL fraction over the 24-h period after a single dose; the reverse was found after multiple dosing. Cyclosporine was not detectable in the very LDL fractions. The percentage of total plasma CSA contained in each lipoprotein fraction was independent of the concentration of CSA in total plasma or whole blood. The pharmacokinetics of CSA in the various biologic matrices were not associated with measurements of kidney and liver function. Taken together, the variability of CSA pharmacokinetics previously reported in whole blood or total plasma was also found in lipoprotein fractions. The relative changes in CSA content of lipoproteins may offer an explanation for differences in drug effect with multiple dosing.

Incidence of microalbuminuria in ambulatory patients with acquired immunodeficiency syndrome.

Nephropathies associated with human immunodeficiency syndrome (HIVAN) are characterized by gross proteinuria, lack of change in blood pressure, and various histologic lesions. The present study prospectively measured microalbuminuria in 72 HIV-seropositive patients (3 asymptomatic, 32 AIDS-related complex, 37 AIDS) screened for Phase I clinical pharmacology studies. There were 14 patients (19.4%) that had abnormal urinary levels of microalbumin; 7 of these patients (50%) had proteinuria similar to those values found in diabetic nephrotic syndrome. Microalbumin levels were not correlated with race, sex, risk factors of AIDS, disease history, or concurrent drug therapy. In contrast, urinary microalbumin levels were correlated with CD 4 T-cell and WBC counts, tumor necrosis factor alpha and beta 2-microglobulin levels, suggesting an association between AIDS progression and microalbuminuria. By monitoring urinary microalbumin levels, those patients susceptible to the development of nephrotic syndrome could be identified and prophylactic measures initiated.

Time-dependent pharmacokinetics and toxicity of cyclosporine.

Although the circadian pattern of cyclosporine (CSA) pharmacokinetics and toxicity has been described previously in both animal and clinical studies, the mechanism of this action is unknown. The present study compared the pharmacokinetics and experimental nephrotoxicity of chronic CSA in both the genetically-hyperlipidemic rat model and the lean litter-mate. Once daily dosing (25 mg/kg via gavage) was either at the start of the active (1900) or inactive (0700) cycle (Nov 1987 to Jan 1988). Serial serum samples following the final dose were assayed by both polyclonal (nonspecific) and monoclonal (specific for parent CSA) RIA. Renal toxicity was assessed by 24-hr creatinine clearances, fractional clearances of sodium and potassium, and inulin clearances (CIN). Despite a greater than 2-fold increase in serum CSA concentrations, there were no changes in renal function in obese rats dosed at the start of the active period compared to the inactive period. Furthermore, mean CIN of the lean group administered drug at the start of the active period was not significantly different from time-matched placebo-treated lean rats. However, there was an 80% drop in CIN in rats treated with CSA at the start of the inactive period compared to control group. There were no differences in electrolyte handling. Insulin concentrations, independent of time of dosing, were markedly elevated in obese rats dosed CSA compared to placebo-treated obese or both lean groups. Serum triglyceride levels were significantly correlated with pharmacokinetic parameters of total but not parent CSA. In summary, significant differences in toxicity were observed due to time of dosing and lipid profiles. Although the mechanism of this action remains unclear, it appears that increased non-fasting serum triglyceride levels following the active period most likely reduced CSA distribution into kidney tissue preventing the dose-limiting nephrotoxicity.