Prescribing medication in long-term dialysis units.

Little information is available regarding the current patterns of medication use in long-term dialysis centers. Therefore, we surveyed the medication records of 1,023 patients undergoing long-term dialysis therapy in 27 dialysis centers. The mean number of medications prescribed per patient was 7.7 +/- 0.54, increasing patient age, increasing duration of dialysis, in-center dialysis, and the presence of underlying diabetic and hypertensive nephropathy were associated with increased frequency of medication use. The use of multiple pharmacologic agents was associated with a high frequency of drug duplication (12%), potential dosage error (9%), potential significant drug interaction (15%), and use of contraindicated drugs (2.5%). A lack of individualization of the use of several pharmacologic agents was apparent. An extreme degree of center variability in drug use was also apparent. Periodic review of medication use should be undertaken in the long-term dialysis setting.

The safety and pharmacokinetics of GLQ223 in subjects with AIDS and AIDS-related complex: a phase I study.

A phase I dose-escalation study was performed to evaluate the safety and pharmacokinetics of a single intravenous infusion of GLQ223 in subjects with AIDS and AIDS-related complex (ARC). The active ingredient in GLQ223 is trichosanthin. Trichosanthin, imported from China, is the active drug in community-initiated treatment programs for patients with HIV infection. Eighteen subjects were enrolled, 10 with AIDS and eight with ARC. All subjects were monitored for tolerance and toxicity. Immunological and virological parameters were also followed. GLQ223 administration was not associated with notable toxicity with the exception of one subject who experienced a severe neurological adverse reaction. No consistent or sustained changes in CD4+ lymphocyte populations or HIV antigen levels were observed. Serum concentrations of GLQ223 that were comparable to concentrations shown to have antiviral activity in vitro were achieved transiently but may not have been maintained for a sufficient duration to exert antiretroviral effects. Further studies are indicated to determine pharmacodynamic properties of GLQ223, its optimal dosing schedule, and whether GLQ223 or related molecules will be useful in the treatment of HIV infection.

Foscarnet-induced hypocalcemia and effects of foscarnet on calcium metabolism.

Foscarnet (trisodium phosphonoformate), an investigational pyrophosphate analog increasingly used to treat refractory cytomegalovirus retinitis and mucocutaneous herpes simplex virus infections in immunocompromised patients, has been reported to cause abnormalities in serum calcium and phosphate, including cases of fatal hypocalcemia. To further elucidate the magnitude and mechanism of these abnormalities in humans treated with foscarnet for opportunistic herpes virus infections, we analyzed anaerobic serum specimens and 24-h urine samples before and after single and multiple doses of iv foscarnet and performed a series of in vitro experiments with normal human serum and plasma. Plasma ionized calcium concentrations acutely decreased by a mean 0.17 mmol/L in the 6 individuals who received a 90 mg/kg dose of foscarnet and by a mean 0.28 mmol/L in the 11 individuals who received a 120 mg/kg dose (P = 0.016, 90 vs. 120 mg/kg dose). Results of in vitro experiments showed a highly significant inverse linear relationship between foscarnet and ionized calcium concentrations, but no correlation between foscarnet and total calcium or phosphate concentration. Dialysis experiments suggested that the complexing of foscarnet with ionized calcium could be a cause of this ionized hypocalcemia. Physicians must be aware of this phenomenon and should measure serum ionized calcium during foscarnet therapy (preferably at the end of a foscarnet infusion) whenever neurological or cardiological abnormalities occur.

Prednisolone disposition in cushingoid and noncushingoid kidney transplant patients.

Little information is available on the disposition of prednisolone in kidney transplant patients and whether correlations exist between the pharmacokinetics and therapeutic or toxic effects of this drug. The present study was designed to determine the pharmacokinetics of prednisolone in six noncushingoid and six cushingoid transplant recipients. The elimination half-lives were not significantly different in the noncushingoid and cushingoid patients (2.3 vs. 3.3 h). However, other pharmacokinetic parameters were significantly lower in the cushingoid group: plasma clearance (147 vs. 82 ml/min) and volume of distribution (32 vs. 20 liters). In addition, the availability of prednisolone after oral prednisone administration was considerably variable (overall range, 27-108%) and was not significantly different between the two groups. Thus, in kidney transplant patients it appears that the plasma clearance and volume of distribution of prednisolone may distinguish between noncushingoid and cushingoid patients.

Zidovudine phosphorylation after short-term and long-term therapy with zidovudine in patients infected with the human immunodeficiency virus.

BACKGROUND: Resistance of human immunodeficiency virus (HIV) to zidovudine (AZT) has been associated with mutations in the viral reverse transcriptase gene. However, recent studies suggest that host cellular factors such as a decreased thymidine kinase activity or an increased cellular P-glycoprotein expression may be important. This study compared concentrations of zidovudine monophosphate, zidovudine diphosphate, and zidovudine triphosphate with P-glycoprotein expression in peripheral blood mononuclear cells from patients receiving long-term (> 18 months) and short-term (< 2 months) zidovudine treatment. METHODS: Ten subjects in the short-term group and 11 subjects in the long-term group with CD4 counts between 300 and 500 received a single oral dose of zidovudine (200 mg) after a 24-hour washout period. Blood samples were collected at 0, 1, 2, 4, and 6 hours. Intracellular nucleotide concentrations were measured by a combined HPLC-radioimmunoassay method, and P-glycoprotein expression was determined by fluorescence activated cell sorting (FACS) analysis with use of the monoclonal mouse antibody MRK-16. RESULTS: Zidovudine monophosphate was the predominant compound, accounting for 73.4% +/- 7.1% (SD) of the total phosphates in the long-term treatment group and 74.2% +/- 15.0% (SD) in the short-term group. Zidovudine diphosphate accounted for 13.3% +/- 3.3% (SD) in the long-term group and 12.5% +/- 6.6% (SD) in the short-term group. Zidovudine triphosphate accounted for 13.4% +/- 4.1% (SD) in the long-term group and 13.5% +/- 8.3% (SD) in the short-term group. Mean peak concentrations for the active zidovudine triphosphate were 0.04 +/- 0.02 (SD) pmol/10(6) cells in both groups. Comparison of the individual zidovudine phosphate concentrations and P-glycoprotein expression revealed no significant difference in the two patient populations. CONCLUSIONS: These data suggest that intracellular phosphorylation does not change over time and that zidovudine does not select for P-glycoprotein expressing cells.

Furosemide kinetics and dynamics after kidney transplant.

We examined differences between responder (R) (40 to 80 mg/day) and nonresponder (NR) (greater than or equal to 120 mg/day) patients after kidney transplant with respect to furosemide kinetics and dynamics. Nonresponders had reduced plasma clearance (NR 64 +/- 21.4 and R 105 +/- 23 ml/min, two-sample t test; p less than 0.05), renal clearance (NR 18.4 +/- 8.1 and R 47.1 +/- 11.0 ml/min; p less than 0.005), and renal clearance to creatinine clearance ratio (NR 0.43 +/- 0.15 and R 0.80 +/- 0.07; p less than 0.005). Half-life rose in the nonresponders (NR 130 +/- 13 and R 87.6 +/- 16.3 min; p less than 0.005). There was no difference between groups with respect to nonrenal clearance, extent of availability, volume of distribution steady state, and the fraction of the dose excreted unchanged in the urine after intravenous administration. These results suggest that nonresponders have less ability to secrete furosemide into tubular fluid as well as less ability to respond to drug.

Hemodialysis of phenytoin in a uremic patient.

Removal of phenytoin by hemodialysis was determined in a uremic patient. The rate of appearance of the drug in dialysate, the plasma concentration with time, and the plasma clearance by dialysis were measured. Plasma protein binding of phenytoin was also determined. In spite of greatly reduced plasma protein binding in the uremic patient, removal rate was observed to be less than 10% of the rate of presentation of the dialyzer. During the 6-hr period of dialysis, the plasma concentration showed little change. The amount collected in the dialyase, 43.6 mg, was only a small fraction of drug in the body. These results indicate that replacement of phenytoin based on the amount of drug removed by dialysis is unnecessary in chronically dialyzed uremic patients. In addition, the utility of hemodialysis in phenytoin overdose is questioned.

Kinetics of oral ethambutol in the normal subject.

Six normal adult volunteers received 15 mg/kg of ethambutol (EMB) by mouth, once as an aqueous solution and again as the commercial tablet preparation. Each dose was separated by at least 7 days. Plasma and urine samples were collected at regular intervals for up to 24 and 72 hr, respectively. Peak plasma concentrations ranged from 3.25 to 5.62 mcg/ml, 2 to 4 hr after tablet dosage. Earlier peak times were found after administering the solution. For plasma concentrations up to 12 hr there was a distinct distribution phase followed by an apparent elimination phase with a mean half-life (t 1/2) (+/- SD) of 4.06 +/- 0.53 and 4.78 +/- 0.41 hr for the tablet and the solution, respectively. Excretion rate plots exhibited similar t 1/2 values for the apparent elimination phase. An even longer t 1/2 of approximately 10 hr was evident from 24-hr plasma samples and urinary excretion measurements up to 72 hr. Unchanged drug excreted in the urine averaged 61.1 +/- 3.8% of the dose for the tablet and 63.4 +/- 2.6% for the solution. Plasma protein binding for ethambutol determined by equilibrium dialysis and ultrafiltration was approximately 20% to 30%. The concentration ratio of ethambutol in erythrocytes to plasma ranged from 1.1 to 1.6.

Influence of coadministration on the pharmacokinetics of mezlocillin and cefotaxime in healthy volunteers and in patients with renal failure.

The pharmacokinetic disposition of cefotaxime, desacetyl cefotaxime, and mezlocillin after the administration of each drug singly and in combination was examined in eight healthy volunteers and in five anuric patients with end-stage renal disease (ESRD). In the presence of ESRD, the total body clearance of cefotaxime decreased from 256.7 +/- 41.5 to 65.4 +/- 42.0 ml/min, and its elimination half-life (t1/2) increased from 1.1 to 3.6 hours as compared with healthy volunteers. Concomitant administration of mezlocillin in healthy volunteers decreased the total body clearance of cefotaxime by 42% and increased its steady-state volume of distribution. This reduction in clearance was reflected by a decrease in both renal and nonrenal clearances. In the presence of ESRD, coadministration of mezlocillin increased the t1/2 of cefotaxime to 5.8 hours. Desacetyl cefotaxime accumulated in ESRD with a prolongation of its elimination t1/2 to 18.7 hours from 1.7 hours in healthy volunteers. Desacetyl cefotaxime peak plasma concentrations occurred later with the combination regimen in the presence of ESRD. The clearance of mezlocillin was reduced and t1/2 prolonged in ESRD from 194.6 +/- 31.9 to 76.4 +/- 38.8 ml/min and 1.4 to 2.3 hours, respectively. Concomitant administration of cefotaxime did not alter the pharmacokinetics of mezlocillin. These data suggest that in the presence of normal renal function, lower doses of cefotaxime may be adequate to maintain similar cefotaxime plasma concentrations when mezlocillin is coadministered compared to when cefotaxime is given alone. Additional pharmacodynamic and clinical studies with this combination are warranted to further elucidate the clinical impact of this pharmacokinetic interaction.

Foscarnet and ganciclovir pharmacokinetics during concomitant or alternating maintenance therapy for AIDS-related cytomegalovirus retinitis.

INTRODUCTION: The use of foscarnet and ganciclovir as a combination treatment for cytomegalovirus retinitis is increasing because of limitations associated with single agent therapy. METHODS: The pharmacokinetics of foscarnet and ganciclovir were determined in 13 patients receiving either concomitant therapy (regimen A) or daily alternating therapy (regimen B) for maintenance of cytomegalovirus disease. For regimen A, 60 mg/kg intravenous foscarnet and 3.75 mg/kg ganciclovir were sequentially administered daily; for regimen B, 120 mg/kg foscarnet and 6 mg/kg ganciclovir were administered on alternating days. For both regimens, serial blood sampling for pharmacokinetic analysis was performed for each drug alone (day 1 or 2) and after 2 weeks of combination therapy. Plasma samples for foscarnet and ganciclovir analysis were performed by means of high-performance liquid chromatography. Pharmacokinetic analysis was performed with noncompartmental methods. RESULTS: For regimen A, the plasma clearance (CL) of foscarnet did not change in the presence of ganciclovir, averaging 0.12 +/- 0.08 and 0.11 +/- 0.02 L/hr/kg on study days 2 and 14, respectively (p = 0.34). The volume of distribution (VSS) and mean residence time (MRT) also did not change significantly. CL and MRT of foscarnet did not change for regimen B, although a slight increase in VSS was observed before (0.38 +/- 0.05 L/kg) and after (0.46 +/- 0.07 L/kg) alternating therapy (p = 0.03). Ganciclovir CL did not change for either regimen, with mean values of 0.21 +/- 0.10 and 0.25 +/- 0.10 L/hr/kg (regimen A, p = 0.17) and 0.32 +/- 0.10 and 0.34 +/- 0.11 L/hr/kg (regimen B, p = 0.24). MRT and VSS were also not significantly different. CONCLUSION: These plasma data suggest that further dosage adjustments are unnecessary for or alternating maintenance therapy.

Cefamandole kinetics in uremic patients undergoing hemodialysis.

A single intravenous 15 mg/kg dose of cefamandole was given to 6 patients in chronic renal failure before hemodialysis, and 3 were examined during an interdialysis period. Mean cefamandole clearance by hemodialysis was 24 +/- 12 ml/min; 35 +/- 15% of the dose was recovered in the dialysate. The cefamandole half-life (1 1/2) on dialysis was 4.0 +/- 0.29 hr; off dialysis it was 13.9 +/- 4.2 hr. High urine concentrations of cefamandole in these patients suggests usefulness in urinary tract infection.

Pharmacokinetics of cidofovir in renal insufficiency and in continuous ambulatory peritoneal dialysis or high-flux hemodialysis.

BACKGROUND: Cidofovir is an antiviral agent used for the treatment of cytomegalovirus infection in patients with acquired immunodeficiency syndrome. Because cidofovir is primarily eliminated by the kidneys and because its main adverse effect is nephrotoxicity, an understanding of the pharmacokinetic disposition of cidofovir in patients with renal insufficiency is necessary. METHODS: Twenty-four subjects were enrolled into this study and were divided into 6 groups depending on their degree of renal dysfunction, including subjects receiving maintenance continuous ambulatory peritoneal dialysis and high-flux hemodialysis. The creatinine clearance (CLCR) for subjects not receiving dialysis ranged from 12 to 164 mL/min. Each subject received a single 0.5 mg/kg intravenous dose of cidofovir over 1 hour. Subjects not receiving dialysis were given intravenous hydration with 1 L normal saline solution and concomitant oral probenecid. Serial serum and urine samples were collected to determine pharmacokinetic parameters with use of noncompartmental methods. RESULTS: Mean +/- SD cidofovir clearance (CL) in control subjects (normal renal function; n = 5) was 1.7 +/- 0.1 mL/min/kg, which decreased with declining renal function as indicated by the regression equation: CL (mL/min/kg) = 0.94 x CLCR (mL/min/kg) + 0.064 (r2 = 0.91). Mean volume of distribution at steady state did not change significantly in subjects with kidney disease and cidofovir serum elimination half-life was significantly increased in subjects with severe renal impairment. Cidofovir was not significantly cleared during continuous ambulatory peritoneal dialysis, but high-flux hemodialysis resulted in the removal of 52% +/- 11% of the dose administered. CONCLUSION: The significant (P < .001) correlation observed between CLCR and CL in subjects with varying degrees of renal insufficiency indicates that aggressive dosage reduction of cidofovir would be necessary in subjects with kidney disease to ensure comparable drug exposure based on serum levels.

The pharmacokinetics of teicoplanin in varying degrees of renal function.

The pharmacokinetics of teicoplanin, a new glycopeptide antibiotic with activity against aerobic gram-positive bacteria, were characterized after intravenous administration of a single 3 mg/kg dose in five healthy volunteers and six patients with various degrees of stable renal insufficiency. Serum and urine samples were collected during a 15-day period and drug concentrations were assayed microbiologically. The mean elimination half-life of teicoplanin was 162.6 +/- 69.8 hours in healthy volunteers and was prolonged with decreased renal function. The mean plasma and renal clearances of teicoplanin in healthy subjects were 11.4 +/- 1.5 ml/min and 10.0 +/- 1.0 ml/min, respectively. Both values decreased in patients with renal failure and correlated significantly with measured creatinine clearances (r2 = 0.938 and 0.884, respectively). A nomogram for dosage adjustment in patients with varying degrees of renal failure is presented.

Teicoplanin pharmacokinetics and bioavailability during peritoneal dialysis.

The pharmacokinetics of teicoplanin in serum and dialysate were examined in a crossover study after intravenous and intraperitoneal administration of a 3 mg/kg dose to five anuric patients who were undergoing continuous ambulatory peritoneal dialysis (CAPD). Blood and dialysate samples were obtained for 30 and 15 days, respectively, and were assayed microbiologically. The principal pharmacokinetic parameters after intravenous administration were as follows: total body clearance, 2.76 +/- 1.08 ml/min; elimination half-life, 377 +/- 109 hours; volume of distribution at steady state, 1.04 +/- 0.18 L/kg. Only 9% +/- 6% of the intravenous dose was recovered in the dialysate and the net peritoneal clearance was 0.25 +/- 0.21 ml/min. Bioavailability values, which were assessed by use of three methods after intraperitoneal administration and while dialysate was retained in the peritoneal cavity for 5 hours (dwell time), were 0.77 +/- 0.21, 0.78 +/- 0.05, and 0.76 +/- 0.08. Changes in bioavailability with dwell time were also examined. A dosing guide, which accounts for changes in bioavailability with dwell time, is presented.

Pharmacokinetics of esmolol and ASL-8123 in renal failure.

The effect of renal function on the pharmacokinetics of esmolol, an ultra-short-acting beta-adrenergic blocker, and its major metabolite, ASL-8123, was examined in six healthy control subjects, six patients maintained on hemodialysis, and six patients on continuous ambulatory peritoneal dialysis (CAPD). In addition, the impact of hemodialysis and CAPD on removal of esmolol and ASL-8123 was determined. Multiple blood, urine, and dialysate samples were collected during a 72-hour period and assayed for esmolol and ASL-8123 by HPLC. The pharmacokinetic disposition of esmolol was not significantly altered by renal failure. Mean (+/- SD) total body clearance for esmolol was 171.4 +/- 69.8, 249.8 +/- 176.3, and 265.3 +/- 143.1 ml/min/kg for the control, hemodialysis, and CAPD patients, respectively. Mean elimination half-life (t1/2) was 7.2 minutes in control subjects compared with 7.1 and 8.0 minutes for the hemodialysis and CAPD groups, respectively. The apparent volume of distribution of esmolol did not differ significantly among the three groups. ASL-8123 was shown to accumulate in patients with renal failure, as evidenced by a mean maximum blood concentration of 42.8 +/- 12.2 micrograms/ml in the control group compared with 76.1 +/- 23.9 and 87.1 +/- 20.4 micrograms/ml in the hemodialysis and CAPD groups, respectively (p less than 0.05). The elimination t1/2 of ASL-8123 was prolonged in patients with renal failure, averaging more than 42 hours compared with only 4 hours in the control subjects. Approximately 20% of the esmolol dose as ASL-8123, was removed by either hemodialysis or CAPD, contributing minimally to the elimination of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of F105, a human monoclonal antibody, in persons infected with human immunodeficiency virus type 1.

F105 is a human monoclonal antibody that binds to the CD4 binding site of human immunodeficiency virus type 1 gp120 and neutralizes clinical and laboratory isolates of the human immunodeficiency virus. This phase I study investigated the disposition of the antibody in humans. F105 was administered over a 60-minute period at two dose levels, 100 and 500 mg/m2. Blood samples were obtained for up to 56 days. The clearance of the antibody was 0.33 ml/min with a corresponding half-life of approximately 13 days. Peak concentrations achieved at the higher dose level were 216.19 +/- 9.62 micrograms/ml. The disposition of the drug was linear for the doses studied. Simulations were performed to design future studies aimed at investigating the efficacy of the antibody. This study concluded that F105 can be administered as a bolus dose every 21 days.

Amdinocillin pharmacokinetics. Simultaneous administration with cephalothin and cerebrospinal fluid penetration.

In the treatment of serious infections, combinations of beta-lactam antibiotics are being utilized in order to avoid aminoglycoside toxicity and to achieve antibacterial synergy. The pharmacokinetic disposition of amdinocillin and cephalothin was determined, when administered alone or in combination to healthy volunteers, as well as the penetration of amdinocillin into human cerebrospinal fluid. Six subjects received, on separate occasions, single intravenous doses of amdinocillin 10 mg/kg, cephalothin 15 mg/kg, or a combination of the two in the same doses. The elimination half-lives of amdinocillin and cephalothin are increased when these drugs are given simultaneously, compared with when they are administered alone. However, no significant differences were observed. When they were given in combination, no significant changes in plasma clearance, renal clearance, or steady-state volume of distribution were found. Eight patients undergoing lumbar puncture for various neurologic disorders without inflamed meninges received a single dose of 10 mg/kg amdinocillin intravenously. One to two hours later, simultaneous plasma and cerebrospinal fluid samples were obtained. The concentration of amdinocillin in the cerebrospinal fluid ranged from approximately 1 to 10 percent of concomitant plasma concentrations. Thus, amdinocillin penetrates in the cerebrospinal fluid in marginal amounts in the absence of meningeal inflammation.

Effect of renal impairment on the pharmacokinetics of grepafloxacin.

Grepafloxacin is mainly (approximately 90%) excreted by nonrenal mechanisms. The effect of renal impairment on the pharmacokinetics of grepafloxacin was evaluated in an open-label study involving 20 adults, 15 of whom had some degree of renal impairment (creatinine clearance 7.5 to 64.0 ml/min). Of these 15, 3 had mild renal impairment, 6 had moderate renal impairment, and 6 had severe renal impairment. Grepafloxacin 400 mg was administered orally once daily for 7 days, and pharmacokinetic parameters were measured on days 1 and 7. The results show that both renal clearance and the amount of grepafloxacin excreted unchanged in urine, on day 1 and day 7, were significantly lower in individuals with severe renal impairment compared with those who were healthy. Renal clearance was 0.50 +/- 0.05 ml/min/kg in healthy individuals vs 0.15 +/- 0.05 ml/min/kg in patients with severe renal impairment on day 1, while the corresponding values on day 7 were 0.46 +/- 0.04 ml/min/kg vs 0.14 +/- 0.08 ml/min/kg, respectively. The percentage of grepafloxacin excreted unchanged in urine on day 1 was 5.1 +/- 3.0 in the healthy individuals and 1.5 +/- 0.7 in those with severe renal impairment. On day 7, the corresponding values were 7.9 +/- 1.9 and 2.9 +/- 2.2. No other significant pharmacokinetic differences occurred between the 2 groups. Accumulation during multiple dose administration did not vary with the degree of renal impairment. We conclude that the pharmacokinetics of grepafloxacin are not significantly different in individuals with varying degrees of renal impairment. Hence, dose adjustment is not necessary during treatment of patients with renal dysfunction.

Acute massive chloral hydrate intoxication treated with hemodialysis: a clinical pharmacokinetic analysis.

A 38-year-old female became comatose and exhibited signs of cardiac toxicity 2 hours after ingestion of approximately 38 Gm chloral hydrate. Hemodialysis was initiated 21 hours after ingestion, using twin coils in series, and was continued for 4.5 hours. Trichloroethanol, the active metabolite of chloral hydrate, was measured in plasma and dialysate. Two hours after ingestion, the plasma level was 330 micrograms/ml (average therapeutic level is 12 micrograms/ml or less). The predialysis level was 216 micrograms/ml and after dialysis declined to 141 micrograms/ml. The pre- and post-plasma half-life values were 35 hours, while on dialysis the half-life was only 6 hours. The average dialysis clearance was 120 ml/minute, and the amount of chloral hydrate removed by dialysis was 5.79 Gm. By the end of dialysis, the patient could respond to verbal commands and was ambulatory 36 hours later. In conclusion, hemodialysis can be a clinically important method of treating chloral hydrate overdose.

Effect of food on the pharmacokinetics of cyclosporine in healthy subjects following oral and intravenous administration.

The pharmacokinetics of cyclosporine were studied in healthy subjects following administration of cyclosporine both orally (10 mg kg-1) and intravenously (4 mg kg-1) without and with high fat meals. Both blood and plasma samples (separated at 37 degrees C) were analyzed for cyclosporine concentration. Blood and plasma clearances of cyclosporine were calculated to be 0.36 and 0.47 L hr-1 Kg-1, respectively, and volume of distribution at steady state was calculated to be 1.21 L Kg-1, when cyclosporine was administered without a high fat meal. Using plasma analysis, the oral bioavailability of cyclosporine was estimated to be 21 and 79%, when administered without and with a high fat meal, respectively. When cyclosporine was administered intravenously together with a high fat meal, both clearance and volume of distribution increased significantly. Blood and plasma clearances of cyclosporine were 0.44 and 0.70 L hr-1 Kg-1, respectively, when cyclosporine was administered along with a high fat meal. We conclude that food not only enhances the absorption of cyclosporine but also enhances its clearance and volume of distribution. The observed variability in clearance, bioavailability, and volume of distribution values for cyclosporine across various pharmacokinetic studies can be partially accounted by the type of food administered and the sampling matrix used for analysis.