Pharmacokinetics and pharmacodynamics of prednisolone following extremely high dosage as prednisolone hemisuccinate

Plasma levels of prednisolone and prednisolone hemisuccinate of volunteers were measured with HPLC following i.v. injections of 1200 and 75 mg of prednisolone, given as the water-soluble hemisuccinate ester. The hemisuccinate ester is hydrolyzed relatively quickly with a plasma half-life between 18 and 25 min, and the resulting prednisolone has a plasma half-life of 3.5-3.7 h. The dose dependency of the pharmacokinetic parameters indicates a partial saturation of the metabolizing enzymes as consequence of the application of the high dose of prednisolone. In saliva no hemisuccinate could be detected. The prednisolone saliva concentration corresponds with those of non-protein-bound prednisolone in plasma measured at the same time. Only minor quantities of intact ester (1-8%) or intact prednisolone (2-4%) are excreted in urine. Following the application of 1200 mg prednisolone the endogenous cortisol level is partially suppressed only 24 h after the i.v. injection; 48 h later the difference from the basis value is not statistically significant. Leukocytosis and granulocytosis are at maximum 24 h after the injection of the high dose, and after 48 h normal values are observed. Lymphocytes and monocytes fall below normal levels for a longer time after 1200 mg compared to 75 mg, the minimum is between 4 and 8 h. Glucose levels are enhanced dose-dependently. They are normalized even after the extremely high dose at 24 h. Sodium, potassium, calcium, plasma proteins, urea, creatinine, hematocrit and hemoglobin showed no significant differences within 48 h following the injections.     

Bioavailability and reversible metabolism of prednisone and prednisolone in man

The pharmacokinetics of prednisone and prednisolone was examined in 12 healthy male subjects to assess the bioavailability and the parameters of reversible metabolism between the two steroids. After an oral prednisone dose of 0.8 mg kg^?1 and an intravenous prednisolone dose of 0.66 mg kg^?1, the bioavailability was found to be about 62%. The fraction of the dose recovered in the urine as the hydroxylated metabolites of prednisone and prednisolone was lower after the oral prednisone dose, suggesting that poor absorption of prednisone was the main cause of the low bioavailability. There was a high degree of interconversion between prednisone and prednisolone with 76% of the dose being recycled. The formation clearance of prednisolone from prednisone is much greater than the formation clearance of prednisone from prednisolone or the irreversible elimination clearances of the two steroids. The possible dose dependences of bioavailability and interconversion may be important factors in prednisolone therapy.     

Bioavailability and disposition of prednisone and prednisolone from prednisone tablets

The relative bioavailability of two 50 mg prednisone tablet formulations was determined in 18 healthy male volunteers who were not pretreated with dexamethasone. Plasma and urine samples were collected over a 24-h period and their concentrations of prednisone and prednisolone were assayed by a specific and sensitive high pressure liquid chromatography (HPLC) method. Bioavailability was assessed by comparing the areas under the plasma concentration-time curves and by the relative amounts of prednisone and prednisolone in urine. There were no significant differences between the bioavailability of the film-coated and standard 50 mg tablets. Eight subjects subsequently received a 40 mg equivalent intravenous dose of prednisolone as prednisolone succinate to provide plasma concentrations of prednisolone similar to concentrations found after oral doses of prednisone. The systemic bioavailability of prednisolone, the active metabolite generated from film-coated and standard prednisone tablets, was estimated to be 0·77±0·15 and 0·80±0·11, respectively. The nonlinear distribution, the interconversion, and the simultaneous elimination of these drugs, however, complicate any assessment of their relative and absolute bioavailability.     

Comparison of the pharmacodynamic effects of deflazacort and prednisolone in healthy subjects

  Objective: Deflazacort, a synthetic oxazoline derivative of prednisolone, has been suggested as having major advantages over other glucocorticoids, as it is claimed to cause fewer adverse effects at equivalent antiinflammatory potency. The assumed equipotency ratio of deflazacort versus other glucocorticoids is critical for this assumption. Methods: In a randomized cross-over study we compared the acute effects of deflazacort and prednisolone on serum cortisol, osteocalcin, insulin and blood cells (eosinophils and lymphocytes) in normal subjects. On seven occasions separated by a wash out period ≥ 1 week all participants received placebo, prednisolone (8 mg, 20 mg, 40 mg) and deflazacort (12 mg, 30 mg, 60 mg). The medication was given orally at 20.00 h as a single dose. Blood was collected at 8.00 h before and after each medication. Log (dose) response relationships were calculated and were used to compare the drugs. Results: The following equipotent dose ratios (mg deflazacort: mg prednisolone) were found: osteocalcin suppression 1.54, cortisol suppression 2.27, suppression of eosinophils 1.14 and lymphocytes 2.77. As parallelism between regression curves was rejected, equipotency could not be calculated for insulin. In 3 subjects even the highest dose of deflazacort failed to suppress serum cortisol. Conclusion: Our study highlights the difficulties of establishing equipotency ratios for glucocorticoids. It casts doubts on the generally assumed equipotency dose ratio of deflazacort vs prednisolone, as both for cortisol and lymphocytes the 95% CI was > 1.2. Thus, reduced adverse effects during deflazacort therapy may be a consequence of lower effective glucocorticoid dosage. Received: 11 December 1995 /Accepted in revised form: 16 March 1996     

Alterations in prednisolone disposition as a result of time of administration, gender and dose.

The disposition of total and free prednisolone has been studied in four male and four female volunteers, each of whom received an intravenous dose of 0.075 mg/kg (low) and 1.5 mg/kg (high) of prednisolone at both 06.00 h and 18.00 h. For the low dose, free prednisolone clearance was 14% lower (P = 0.012) and time-averaged prednisolone free fraction was 22% higher (P less than 0.001) in the morning, there being no circadian difference in total prednisolone clearance. There was no circadian differences in prednisolone disposition at the high dose. These findings are consistent with a mechanism in which cortisol causes a simultaneous competitive inhibition of prednisolone clearance and plasma protein binding at low, but not at high prednisolone doses. Prednisolone clearance was higher in female than in male subjects, the mean increase being 18% (P = 0.022) for total prednisolone and 21% (P = 0.036) for free prednisolone. Mean total prednisolone clearance and steady-state distribution volume were two-fold higher at the high vs the low dose (P less than 0.001), but free prednisolone clearance showed a dose dependent decrease of 11% (P = 0.019). There was no change in free prednisolone steady-state distribution volume.     

Alterations in prednisolone disposition as a result of oral contraceptive use and dose.

The disposition of total and free prednisolone has been studied in eight female subjects who used combined oestrogen-progestogen oral contraceptives and in eight female subjects who did not, each of whom received separate intravenous doses of 0.1 mg/kg (low) and 1.0 mg/kg (high) of prednisolone. Mean free prednisolone clearance was reduced congruent to 30% in oral contraceptive users compared to control subjects (P less than 0.001), the difference being greater for the low dose (39%) than for the high dose (24%). Pre-dose plasma cortisol concentrations were elevated two-fold (P less than 0.001) in oral contraceptive users compared to control subjects. These effects are consistent with a mechanism in which the competitive inhibition of free prednisolone clearance by cortisol contributes to the reduction of free prednisolone clearance by oral contraceptive use. Mean total prednisolone clearance and steady state distribution volume showed an approximate two-fold dose dependent increase consistent with a similar increase in plasma prednisolone free fraction (P less than 0.001). Free prednisolone clearance showed an 18% dose dependent decrease (P less than 0.001) but free steady-state distribution volume did not change with dose. At plasma prednisolone concentrations less than 400 ng/ml, prednisolone free fractions at any prednisolone concentration were greater after the low, than after the high dose. This effect is consistent with the displacement of prednisolone by cortisol from transcortin but not from albumin.     

Pharmacokinetics of triamcinolone acetonide and its phosphate ester

Summary Triamcinolone acetonide in the form of its phosphate ester was given intravenously in two different doses (10 mg/kg and 80 mg). Plasma levels of the ester and triamcinolone acetonide were measured and pharmacokinetic parameters were calculated. The pharmacokinetics both of the phosphate and the free alcohol were dose-dependent. No unchanged ester was found in the urine, indicating complete conversion of the pro-drug. Triamcinolone was not a major metabolite of triamcinolone acetonide in humans. Renal clearance was low and independent of the dose. Only about 1% of the dose was found in the urine as triamcinolone acetonide.     

Pharmacokinetics of prednisolone and its local anti-inflammatory steroid-21-oate ester derivatives. In vitro and in vivo comparative study

A new class of local anti-inflammatory steroid-21-oate esters synthesized by modifying the ketol side chain of prednisolone was found to exhibit minimal systemic side effects such as pituitary-adrenal suppression. It has been hypothesized that the absence of the systemic toxicities of these steroids is due to the rapid hydrolysis of the carboxylate ester group to inactive and readily excretable acid metabolites. The pharmacokinetics of prednisolone and its two ester derivatives, methyl 20 alpha- and 20 beta-dihydroprednisolonate (P4 alpha and P4 beta), were studied in rats following im administration of doses ranging from 0.5 to 10 mg/kg. The absorption of each of the three compounds was rapid, as the peak concentration was attained within 20 min after injection. The elimination half-lives of P4 alpha, P4 beta, and prednisolone were independent of dose and were 1.12, 0.28, and 0.53 hr at 10 mg/kg doses, respectively. The AUCs of P4 alpha, P4 beta, and prednisolone following a 10 mg/kg dose were 7678, 242, and 3037 ng/ml.hr, respectively. The pharmacokinetics of the P4 alpha were linear as the AUC increased proportionally with dose. An in vitro study showed that P4 beta was approximately 100% hydrolyzed within 1 hr in plasma at 37 degrees C, whereas P4 alpha was about 30%. However, a negligible disappearance of prednisolone occurred in vitro over a period of more than 2 days. These results suggest that the minimal systemic side effects of these new steroids may be ascribed to the differences in their pharmacokinetic profiles and metabolism from those of prednisolone.     

Dose-dependent pharmacokinetics of prednisolone in normal and adrenalectomized rats

The pharmacokinetics of prednisolone after 5- and 50-mg/kg doses given as the sodium succinate salt was examined in normal and adrenalectomized rats. Prednisolone, prednisone, and corticosterone concentrations in plasma were determined by HPLC and free prednisolone measured by equilibrium dialysis. Prednisolone sodium succinate was rapidly and completely hydrolyzed to prednisolone as indicated by the absence of the ester from plasma within 5 min after intravenous injection. Prednisolone was rapidly metabolized to prednisone, while corticosterone concentrations in normal rats declined rapidly and were undetectable by 1 hr. Adrenalectomy had no effect on the disposition and protein binding of prednisolone. Dose, however, had a marked effect on prednisolone pharmacokinetics, with mean plasma clearance decreasing from 6.18 to 3.07 L/h per kg and mean steady-state volume of distribution decreasing from 2.14 to 1.05 L/kg from the lower to higher steroid dose. Half-life (0.50 hr) and mean residence time (0.35 hr) were unaffected by dose. Prednisolone plasma protein binding was nonlinear due to saturation of transcortin binding. Changes in pharmacokinetic parameters were not related to the nonlinear plasma binding, but were more likely caused by saturation of elimination pathways and tissue binding sites.     

Dose dependent pharmacokinetics of prednisone and prednisolone in man

Six healthy male volunteers were given 5, 20, and 50 mg of oral prednisone and 5, 20, and 40 mg doses of intravenous prednisolone. Plasma and urine concentrations of prednisone and prednisolone were determined by HPLC, and the binding of prednisolone to plasma proteins was measured by radioisotopic and equilibrium dialysis techniques. The pharmacokinetics of both oral prednisone and intravenous prednisolone were dose-dependent. The mean oral dose plasma clearances of prednisone ranged from 572 ml/min/ 1.73 m ² for the 5mg dose to 2271 ml/min/1.73 m ² for the 50 mg dose. Changes in prednisone half-life were insignificant, but increases in the half-life of its metabolite were dose-dependent. The systemic plasma clearance of i.v. prednisolone was dose-dependent and increased from 111 to 194 ml/min/1.73 m ² over the 5 to 40 mg i.v. dosage range. The steady-state volume of distribution also increased, but little change in mean transit time and half-life was found. The binding of prednisolone to plasma proteins was markedly concentration-dependent, and a two compartment, nonlinear equation was used to characterize the effective binding of prednisolone to transcortin and albumin. The apparent pharmacokinetic parameters of protein-free and transcortin-free prednisolone were relatively constant with dose. The interconversion of prednisone and prednisolone varied with time and dose, although prednisolone concentrations dominated by 4-to 10-fold over prednisone. In urine, 2–5% of either administered drug was excreted as prednisone and 11–24% as prednisolone. The apparent renal clearances of both steroids were also nonlinear and unrelated to protein binding. These studies indicate that the pharmacokinetics of prednisone and prednisolone are dose-dependent and that protein binding does not fully explain their apparent nonlinear distribution and disposition.This work was supported in part by Grant 24211 from the National Institutes of General Medical Sciences, National Institutes of Health.     

Time course of the changes in prednisolone pharmacokinetics after co-administration or discontinuation of rifampin

Summary We have investigated changes in the pharmacokinetics of prednisolone caused by co-administration or discontinuation of rifampin.Serial IV pharmacokinetic studies of prednisolone (1 mg/kg) in groups of 3 patients over a 1 month period of rifampin co-treatment or after its withdrawal, revealed significant changes in the area under the curve, the total clearance, the non-renal clearance and the half-life. The changes in the pharmacokinetic parameters reached a 1.5 to 2-fold plateau after 2 weeks and the half maximal effect was attained within 5 days. Neither the volume of distribution nor the protein binding of prednisolone were significantly altered.     

Dose-dependent pharmacokinetics of prednisolone in normal and adrenalectomized rats

The pharmacokinetics of prednisolone after 5- and 50-mg/kg doses given as the sodium succinate salt was examined in normal and adrenalectomized rats. Prednisolone, prednisone, and corticosterone concentrations in plasma were determined by HPCL and free prednisolone measured by equilibrium dialysis. Prednisolone sodium succinate was rapidly and completely hydrolyzed to prednisolone as indicated by the absence of the ester from plasma within 5 min after intravenous injection. Prednisolone was rapidly metabolized to prednisone, while corticosterone concentrations in normal rats declined rapidly and were undetectable by 1 hr. Adrenalectomy had no effect on the disposition and protein binding of prednisolone. Dose, however, had a marked effect on prednisolone pharmacokinetics, with mean plasma clearance decreasing from 6.18 to 3.07 L/h per kg and mean steady-state volume of distribution decreasing from 2.14 to 1.05 L/kg from the lower to higher steroid dose. Half-life (0.50 hr) and mean residence time (0.35 hr) were unaffected by dose. Prednisolone plasma protein binding was nonlinear due to saturation of transcortin binding. Changes in pharmacokinetic parameters were not related to the nonlinear plasma binding, but were more likely caused by saturation of elimination pathways and tissue binding sites.Supported in part by grant GM-24211 from the National Institutes of General Medical Sciences, NIH.     

Dose dependent pharmacokinetics of prednisolone

Summary The pharmacokinetics of prednisolone elimination have been studied in both arthritic patients and normal volunteers using tritiated prednisolone alone, and in conjunction with unlabelled prednisolone in doses of 0.15 mg·kg^–1 and 0.3 mg·kg^–1 body weight. With increasing dose there is prolongation of the plasma half-life and increase in the volume of distribution and plasma clearance of prednisolone. It is proposed that these changes in pharmacokinetic parameters may be associated with non-linear binding of the steroid to plasma proteins.     

Quantitative determination of captopril and prednisolone in tablets by FT-Raman spectroscopy

A procedure for the quantitative determination of captopril and prednisolone in commercial tablets based on partial least squares (PLS) and principal component regression (PCR) treatment of FT-Raman spectroscopic data is described. In the studied medicines active pharmaceutical ingredients (APIs) constitute 4.2–16.7% of the tablet mass. Results obtained from calibration models built using unnormalised spectra were compared with the values found when an internal standard was added to each sample and the spectra were normalised by its selected band intensity at maximum or integrated. To apprise the quality of the models the relative standard error of predictions (RSEPs) were calculated for calibration and testing data sets. For captopril determination these were 1.8–2.2% (2.1–2.3%) and 2.7–3.1% (2.7–3.6%), respectively for the different PLS (PCR) models. For prednisolone these errors amounted to 1.8–2.1% (2.6–3.5%) and 3.2–3.7% (3.7–5.9%), respectively. Three commercial preparations of captopril containing 12.5 mg and one 25 mg of API per tablet were quantified using developed models. Found captopril contents, calculated versus results of iodometric titration, was equal 99.2–101.2% (99.2–102.0%), for the different PLS (PCR) calibration models and the different preparations. Quantification of prednisolone tablets, declared content 5 mg per tablet, on the basis of PLS (PCR) models gave API amount, calculated versus results of UV–vis method, in the 99.0–101.0% (98.0–102.0%) range.     

The effect of itraconazole on the pharmacokinetics and pharmacodynamics of oral prednisolone

Objective: To examine the possible effect of itraconazole on the pharmacokinetics and pharmacodynamics of orally administered prednisolone. Methods: In this double-blind, randomised, two-phase cross-over study, ten healthy subjects received either 200 mg itraconazole or placebo orally once a day for 4 days. On day 4, 20 mg prednisolone was given orally. Plasma concentrations of prednisolone, cortisol, itraconazole, and hydroxyitraconazole were determined by means of high-performance liquid chromatography up to 47 h. Results: Itraconazole increased the total area under the plasma prednisolone concentration–time curve by 24% (P < 0.001) and the elimination half-life of prednisolone by 29% (P < 0.001) compared with placebo. The peak plasma concentration and time to the peak of prednisolone were not affected by itraconazole. The mean morning plasma cortisol concentration, measured 23 h after the ingestion of prednisolone, during the itraconazole phase was 73% of that during the placebo phase (P < 0.001). Conclusions: The observed minor interaction between itraconazole and oral prednisolone is probably of limited clinical significance. The susceptibility of prednisolone to interact with CYP3A4 inhibitors is considerably smaller than that of methylprednisolone, and itraconazole and probably also other inhibitors of CYP3A4 can be used concomitantly with prednisolone without marked changes in the effects of this corticosteroid. Received: 4 October 1999 / Accepted in revised form: 29 November 1999     

Receptor-mediated prednisolone pharmacodynamics in rats: model verification using a dose-sparing regimen

Our receptor/gene-mediated model of corticosteroid action was tested and extended by examining the pharmacokinetics/dynamics of multiple low doses vs. a single higher dose of intravenously administered prednisolone in adrenalectomized male Wistar rats. Low-dose rats received 3 bolus doses (5 mg/kg) of prednisolone at 0, 0.5 and 1.0 hr. High-dose animals were given a single 25 mg/kg dose of prednisolone. Both regimens were expected to produce equivalent net responses based on model predictions. Control rats were not dosed. The profiles of free hepatic cytosolic glucocorticoid receptors and the hepatic tyrosine aminotransferase (TAT) enzyme were examined. Plasma prednisolone concentrations showed bi-exponential decline for both doses using pooled animal data. Clearance of total plasma prednisolone was 4.16 and 3.21 L/hr per kg in low- and high-dose groups. Volume of distribution at steady state (approximately 1.50 L/kg) and central volume (approximately 0.6 L/kg) were similar for both groups. Receptor levels from 5-16 hr stabilized at 64% of the 0-hr control value. Receptor and TAT profiles were essentially superimposable for both dosing groups. Our previous model was used to simultaneously describe prednisolone plasma concentrations, hepatic receptors, and TAT activity. The ability of total plasma prednisolone (Cp), corticosteroid binding globulin (CBG)-free plasma prednisolone (CCBG), and free plasma prednisolone (CF) to describe the kinetics/dynamics were examined. The CF values produced optimum fitting of all receptor data. The similarity of the two dosing groups supports the view that appropriately timed doses of a steroid can be used in an optimally efficacious manner by first filling all receptor sites and then replacing steroid as receptors are expected to recycle from nuclear/DNA binding sites as the steroid is eliminated.     

Evaluation of dose-related pharmacokinetics and pharmacodynamics of prednisolone in man.

The pharmacokinetics and pharmacodynamics of prednisolone were evaluated in normal male volunteers. Seven subjects completed 3 phases: 16.4- and 49.2-mg iv prednisolone, and a phase with no drug to assess baseline responses. Plasma concentrations of prednisolone and urine concentrations of prednisolone and 5 metabolites were assayed by HPLC. Protein binding of prednisolone was measured by ultrafiltration. The polyexponential disposition of free and total plasma prednisolone were evaluated and apparent parameters were compared between doses. Suppression of plasma cortisol and alterations in blood basophil and helper-T cell trafficking were used as pharmacodynamic indices. Pharmacodynamic models were used to relate total or free plasma prednisolone concentrations to each of these effects generating response parameters and IC50 (50% inhibitory) concentrations common to both doses. The pharmacokinetics of total drug were comparable to previous findings with CL and Vss increasing with dose. Free prednisolone exhibited slight capacity-limited elimination and distribution as CL and Vss decreased with the larger dose. Pharmacodynamic models jointly fitting all three phases characterized the suppression/trafficking phenomena equally well with use of total or free drug concentrations. In each case the models provided realistic values of parameters relating to steroid sensitivity--in particular IC50--and to the underlying physiology of the affected systems. This study comprehensively elucidates the complexities of prednisolone pharmacokinetics and demonstrates how plasma concentration--time profiles of total or free prednisolone can be utilized for evaluation of prednisolone pharmacodynamics.     

The effect of SBE4-β-CD on i.m. prednisolone pharmacokinetics and tissue damage in rabbits: Comparison to a co-solvent solution and a water-soluble prodrug

The i.m. pharmacokinetics of prednisolone (5 mg/kg) in eight rabbits after its administration in a co-solvent (40:10:50; PEG 400/ethanol/water) mixture, in a slightly hypertonic 0.09 M SBE4-β-CD (a sulfobutyl ether derivative variably substituted on the 2-, 3- and the 6-positions of β-cyclodextrin) solution and from a water-soluble prodrug, the 21-phosphate ester, disodium salt were studied. Muscle damage as measured by changes in plasma creatine kinase (CK) levels caused by the administration of the three solutions was also assessed. The prednisolone plasma AUC values over 24 h from the SBE4-β-CD formulation and the phosphate ester were 87.0 ± 12.6 and 78.0 ± 14.1% of that from co-solvent, respectively. The apparent bioavailability of prednisolone over 24 h from the SBE4-β-CD formulation and its prodrug was not significantly different from that of the co-solvent. The changes in CK levels from the SBE4-β-CD were identical to those from normal saline, however, the co-solvent mixture caused significantly elevated CK levels. The presence or absence of prednisolone had no effect on the relative CK levels for the cyclodextrin solution and the normal saline. There was a small effect noted for the co-solvent, with and without prednisolone. These results confirm that i.m. administered drugs, such as prednisolone, appear to be rapidly, quantitatively and safely released from SBE4-β-CD inclusion complexes. SBE4-β-CD may provide an alternative to the use of co-colvents and possibly even prodrugs for the i.m. delivery of sparingly water-soluble drugs such as prednisolone.     

Effect of the anti-inflammatory agent tenidap on the pharmacokinetics and pharmacodynamics of prednisolone.

The effect of tenidap, a new nonsteroidal anti-inflammatory agent, on the pharmacokinetics and pharmacodynamics of prednisolone was studied in healthy male subjects. In a randomized crossover study, 12 subjects received either tenidap sodium 120 mg daily or placebo orally for 28 days. On day 21, each subject received a single dose of either 0.8 mg/kg oral prednisone or 0.66 mg/kg intravenous prednisolone followed by the other steroid on day 28. Blood and urine samples were collected, and the pharmacokinetic parameters of prednisone and prednisolone were determined in each treatment period. Pretreatment with tenidap did not cause any significant changes in the overall disposition of prednisone or prednisolone. For example, for free prednisolone, the intravenous area under concentration was 1,144 +/- 195 ng.h/mL and 1,244 +/- 140 ng.h/mL, and the systemic availability after oral prednisone was 53 +/- 10% and 51 +/- 12% with placebo and tenidap, respectively. The renal clearance of prednisolone was significantly reduced after tenidap pretreatment, however (from 143 to 77 mL/min/1.73 m2). The suppression of plasma cortisol and whole blood histamine levels were analyzed to evaluate the potential pharmacodynamic interactions between tenidap and prednisolone. There were no significant changes in the pharmacodynamic parameters between placebo and tenidap groups. The excretion of less than 20% of the dose of prednisolone in urine makes the overall effects of tenidap on prednisolone kinetics and dynamics of inconsequential clinical importance.     

Removal of prednisone and prednisolone by plasma exchange

The effect of plasma exchange on the pharmacokinetics of prednisone and prednisolone was studied. Two patients undergoing plasma exchange while receiving oral prednisone therapy were studied. Patient 1 received prednisone 50 mg daily; patient 2 received 60 mg daily. On a day when the patients were to undergo plasma exchange, blood samples for determination of prednisone and prednisolone concentrations were obtained just before the daily prednisone dose and at various times before, during, and after plasma exchange. The amount of both drugs in plasma removed by plasma exchange was also determined. On a day when the patients were not receiving plasma exchange therapy, additional blood samples were obtained just before the daily prednisone dose and at 0.5, 1, 2, 4, 6, and 8 hours after the dose. Values for elimination rate constant, half-life, area under the curve, clearance, and volume of distribution on and off plasma exchange were calculated from serum concentration-time curves for prednisone and prednisolone. Only prednisolone data proved adequate for pharmacokinetic calculations. Values of pharmacokinetic variables for prednisolone on and off plasma exchange did not differ substantially in either patient. The amount of combined prednisone and prednisolone removed by plasma exchange in each patient was less than 1% of the administered prednisone dose. In the two patients studied, changes in pharmacokinetic values for prednisolone attributable to plasma exchange and the amount of combined prednisone and prednisolone removed by plasma exchange were minimal. Supplemental dosing of prednisone following plasma exchange appears unnecessary.