Pharmacokinetics Of Prednisone Research Articles

Prednisolone and Prednisone Pharmacokinetics in Adult Renal Transplant Recipients.

Prednisolone (PL) is a standard component of most immunosuppressive protocols after solid organ transplantation (Tx). Adverse effects are frequent and well known. The aim of this study was to characterize the pharmacokinetics (PKs) of PL and prednisone (PN), including cortisol (CL) and cortisone (CN) profiles, after PL treatment in renal Tx recipients in the early post-Tx phase. This single-center, prospective, observational study included stable renal Tx recipients, >18 years of age, and in the early postengraftment phase. Blood samples were obtained predose and during a 24-hour dose interval [n = 26 samples per area under the curve (AUC0-24)], within the first 8 weeks post-Tx. PL, PN, CL, and CN concentrations were measured using high-performance liquid chromatography-tandem mass spectrometry. In renal Tx recipients (n = 28), our results indicated a relatively high PL exposure [median, range AUC0-24 = 3821 (2232-5382) mcg h/L], paralleled by strong suppression of endogenous CL profile, demonstrated by a low CL evening-to-morning ratio [median, range 11 (3-47)%]. A negative correlation (r = -0.83) between PL AUC0-24 and morning CL levels was observed. The best single PK variable to predict PL AUC0-24 was PL C6 (r2 = 0.82). An algorithm based on 3 PK sampling time points: trough, 2, and 4 hours after PL dosing, predicted PL AUC0-24 with a low percentage prediction error (PPE = 5.2 ± 1.5%) and a good correlation of determination (r2 = 0.91). PL AUC0-24 varied 3-fold among study participants, whereas CL AUC0-24 varied by 18-fold. The large interindividual variability in both PL exposure and suppression of endogenous CL implies a possible role for therapeutic drug monitoring. An abbreviated profile within the first 4 hours after PL dosing provides a good prediction of PL exposure in renal Tx recipients. The strong negative correlation between PL AUC0-24 and morning CL levels suggests a possible surrogate marker for drug exposure for further evaluation.

Pharmacokinetics of Oral Prednisone at Various Doses in Dogs: Preliminary Findings Using a Naïve Pooled-Data Approach.

This pilot study aimed to determine the plasma pharmacokinetics of prednisone and its active metabolite prednisolone following oral prednisone administration in dogs—using dosing regimens that cover anti-inflammatory to immuno-suppressive biological effects. Six healthy Beagle dogs were given 0.5, 1, 2, and 4 mg/kg prednisone orally once daily for 5 days, each successive course separated by a washout period of 9 days. At steady-state (Day 4), a sparse sampling design allowed for collection of blood from 2/6 individuals for each of the following time points: 0, 15, 30, 60, 90, 120, 240, 480, and 720 min. Prednisone and prednisolone were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Oral prednisone was rapidly converted to prednisolone in dogs (≤ 30 min), with plasma prednisolone reaching ~6-fold greater levels (0–656.1 ng/mL) than prednisone (0–98.8 ng/mL) overall. The ratio of plasma prednisolone/prednisone was constant across the dosing regimens, indicating a non-saturation of the hepatic 11-β-hydroxysteroid dehydrogenase that converts the prodrug to the active metabolite in dogs. The level of both corticosteroids increased with increasing dosing regimens, albeit in a non-linear manner. Non-compartmental pharmacokinetic parameters are described, including peak concentration (Cmax), time of peak concentration (Tmax), area under the concentration-time curve (AUClast), and the elimination half-life (t 1/2) for both corticosteroids, as well as clearance and volume of distribution during the terminal phase (Vz) for the administered drug (prednisone). In sum, the present study utilizes a sparse sampling and naïve pooled-data approach to estimate pharmacokinetic parameters for prednisone and prednisolone, providing supporting preliminary knowledge that can be used to optimize corticosteroid efficacy and minimize toxicity in canine patients.

Prednisone Pharmacokinetics During Pregnancy and Lactation.

To evaluate the steady-state pharmacokinetics of prednisone and its metabolite prednisolone in pregnant and lactating female subjects, 19 subjects received prednisone (4-40 mg/day orally) in early (n=3), mid (n=9), and late (n=13) pregnancy as well as postpartum with (n=2) and without (n=5) lactation. Serial blood and urine samples were collected over 1 dosing interval. Prednisone and its metabolite, prednisolone, steady-state noncompartmental pharmacokinetic parameters were estimated. During pregnancy, prednisone apparent oral clearance increased with dose (35.1±11.4 L/h with 5 mg, 52.6±5.2 L/h with 10 mg, and 64.3±6.9 L/h with 20 mg, P=.001). Similarly, unbound prednisone apparent oral clearance increased with dose. In addition, prednisolone renal clearance increased with dose (0.3±0.3 L/h with 5 mg, 0.5±0.4 L/h with 10 mg, and 1.3±1.1 L/h with 20 mg, P=.002). Higher prednisone (r=0.57, P ≤.05) and prednisolone (r=0.75, P ≤.05) concentrations led to a higher percentage of unbound drug. Breast-milk/plasma area under the concentration-time curve ratios were 0.5-0.6 for prednisone and 0.02-0.03 for prednisolone. Relative infant doses were 0.35% to 0.53% and 0.09% to 0.18%, for prednisone and prednisolone, respectively. Prednisone and prednisolone exhibit dose- and concentration-dependent pharmacokinetics during pregnancy, and infant exposure to these agents via breast milk is minimal.

Prednisolone and Prednisone Pharmacokinetics in Pediatric Renal Transplant Recipients-A Prospective Study.

Prednisolone is a standard component of immunosuppressive protocols in renal transplantation (Tx) and despite standardized treatment regimens, adverse side effects are still frequent. The aim of this study was to characterize the pharmacokinetics of prednisolone and prednisone in pediatric renal transplant recipients in the first 52 weeks post Tx, to describe the relationship between prednisolone and prednisone, and to investigate a possible relationship between the development of new-onset diabetes after Tx (NODAT) and glucocorticoid exposure. Renal transplant recipients receiving prednisolone (n = 11, age 1-15 years) were included in this prospective open-label, descriptive, nonrandomized, and noninterventional study. Blood samples were drawn pre-Tx and during selected dose intervals (0, 1, 2, 4, 6, and 12 hours postdose; less frequent in children <10 kg) at 1, 2, 3, 4, 12, and 52 weeks post-Tx. Concentrations of prednisolone and cortisol, their inactive keto forms, plus methylprednisolone, were measured using a validated LC-MS/MS method. Genetic variants in the CYP3A4, CYP3A5, ABCB1, and HSD11B2 genes were analyzed using real-time polymerase chain reaction and Sanger sequencing. Correlation with NODAT was investigated. The patients displayed considerable intra- and inter-individual variability in prednisolone exposure, with up to 5-fold differences in the area under the concentration-time curve (AUC). There were up to 7-fold differences in prednisolone/prednisone AUC ratio between patients, and patients experiencing NODAT tended to have a higher ratio (>12) compared with patients without NODAT (<12). Genetic variants in CYP3A5 and ABCB1 were found, but due to the limited study population causality cannot be definitive. The study suggests that a high prednisolone/prednisone AUC ratio may be a possible risk factor for NODAT. Further studies of individualization of glucocorticoid treatment in pediatric organ Tx are warranted.

Lack of Pharmacokinetic Interaction Between St. John's Wort and Prednisone

St. John's wort (SJW) is a popular dietary supplement involved in numerous dietary supplement-drug interactions with prescription and non-prescription drugs. The supplement has been shown to affect the metabolism of various CYP3A4 substrates. The CYP3A4 pathway mediates the metabolism of a large number of drug entities, including the corticosteroids prednisone and prednisolone. To examine the effects of long-term SJW administration on the pharmacokinetics of prednisone and its reversible metabolite prednisolone in male subjects. Eight male subjects participated in this single-dose study. The pharmacokinetics of prednisone and prednisolone were evaluated before and after 28 days of SJW administration. Plasma corticosteroid concentrations were determined using a normal phase high-performance liquid chromatography assay. Model-independent methods were used to evaluate corticosteroid pharmacokinetics. Twenty-eight days of SJW treatment resulted in no significant alterations in the pharmacokinetic parameters for prednisone or prednisolone. Oral administration of prednisone resulted in prednisone mean +/- SD area under the curves (AUCs) of 115.89 +/- 39.52 microg x h/L prior to SJW treatment and 128.76 +/- 32.71 microg x h/L after 28 days of treatment. Prednisolone mean AUCs were 714.19 +/- 153.29 microg x h/L before SJW administration and 700.74 +/- 89.68 microg x h/L after treatment. Concurrent administration of SJW had no significant effect on the single-dose pharmacokinetics of prednisone or metabolic prednisolone in male subjects.

Pharmacokinetics of prednisone and prednisolone in a case of hypothyroidism: Effect of replacement therapy

We found this particular case during the course of a clinical trial designed to assess the pharmacokinetics of oral prednisone in normal and diseased children. The plasma concentrations of prednisone, its main metabolite prednisolone, and endogenous cortisol were measured by HPLC at selected times during 8-h periods starting at 7:30 a.m. One 9.9-year-old administered prednisone 0.5 mg/kg p.o. was found to be hypothyroid (TSH: 351 μIU/mL; fT4: <2 pg/mL; fT3: <1 pg/mL); four age-matched normal boys (aged 6.6 ± 4.9 years) served as a control group. In comparison with the controls, the hypothyroid boy showed a marked increase in the total AUC of prednisone (3360 μg h/L versus 215 ± 83 μg h/L) and prednisolone (4040 μg h/L versus 724 ± 77 μg h/L), and an altered pattern of endogenous cortisol, which is known to be impaired in hypothyroid subjects. After 6 months of thyroxine replacement therapy (75 μg/day), the AUCs of prednisone and prednisolone returned to normal values (prednisone: 248 μg h/L; prednisolone: 528 μg h/L), as did the pattern of circadian cortisol secretion. In conclusion, our data indicate that the pharmacokinetics of prednisone and prednisolone can be profoundly altered by hypothyroidism, and subsequently restored by thyroxine replacement therapy.

Bioavailability and activity of prednisone and prednisolone in the feline patient

The purpose of this study was to determine if there is a difference between the pharmacokinetics of prednisone and prednisolone when given orally to cats. Recommendations in current literature are based on clinical opinions, as the bioactivity and bioavailability of prednisone and prednisolone have not yet been determined in cats. Six adult cats were utilized for this study. A three‐dose crossover trial was performed with a 14‐day wash‐out period between each treatment. The three treatment groups consisted of: treatment 1, oral prednisone tablets (a one‐time dose of 10 mg); treatment 2, oral prednisolone tablets (a one‐time dose of 10 mg); and treatment 3, intravenous prednisolone (a one‐time dose of 10 mg). Anaesthesia was performed with isoflurane gas, and a single‐lumen jugular intravenous catheter was placed. The animals were allowed to recover for 1 day before starting the treatment protocol. On day 1, all animals received one of the three treatments. Following intravenous treatment, blood samples of 1.5 mL were drawn immediately prior to drug administration and post‐treatment at 1, 3, 6, 12, 18, 30 and 45 min, and 1, 1.5, 2, 2.5, 6, 12, 24 and 36 h. Following oral treatments, blood samples of 1.5 mL were drawn immediately prior to drug administration and post‐treatment at 7, 18 and 30 min, and 1, 2, 4, 6, 12, 24 and 36 h. The serum samples were collected and frozen at –70oF for shipment to the laboratory for analysis of serum concentrations of prednisone and prednisolone. This procedure was repeated until all cats had gone through the three treatment groups. Determination of glucocorticoid concentrations in feline serum was performed using HPLC mass spectrum analysis. Serum prednisolone levels were measured, as prednisone needs to be converted by the liver to the active form prednisolone. Results revealed that when oral prednisolone was given, serum prednisolone pharmacokinetics were: mean half‐life for absorption = 0.47 h, mean half‐life for excretion = 0.66 h, mean area under the curve (AUC) = 3230.55 ng/mL/h, mean time to maximum serum concentration (Tmax) = 0.77 h, and mean maximum serum concentration (Cmax) = 1400.81 ng/mL. When oral prednisone was given, serum prednisolone pharmacokinetics were: mean half‐life for absorption = 0.90 h, mean half‐life for excretion = 2.46 h, mean AUC = 672.63 ng/mL/h, mean Tmax = 1.44 h, and mean Cmax = 122.18 ng/mL. A paired t‐test was also performed to compare the Cmax and AUC of serum prednisolone, for prednisone vs. prednisolone given orally. These calculations revealed that the Cmax values of serum prednisolone were significantly greater for oral prednisolone than oral prednisone (P = 0.001), and that the reported AUC values were significantly different at P = 0.016. These differences may be due to decreased gastrointestinal absorption of prednisone vs. prednisolone, or to decreased hepatic conversion of prednisone to prednisolone in cats. These data indicate that oral prednisolone is the superior choice for cats. Funding: The Companion Animal Fund, Michigan State University.

Rifampin-Induced Nonresponsiveness of Giant Cell Arteritis to Prednisone Treatment

Rifampin is an enzymatic inducer known to increase steroid metabolism. We studied two patients with giant cell arteritis in whom rifampin caused nonresponsiveness to prednisone treatment. A prednisone pharmacokinetics study was done. When rifampin-prednisone treatment must be used in giant cell arteritis, we propose increasing the prednisone dosage to 2 mg/kg per day.

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.

Optimisation of immunosuppressive therapy using pharmacokinetic principles.

Clinical experience with immunosuppressive therapy is more extensive in the area of preventing the rejection of transplanted organs than in the treatment of autoimmune diseases. Among the many pharmacological agents presently in use, only prednisone (or methylprednisolone) and cyclosporin require dosage individualisation. Sources of interindividual variability in the pharmacokinetics of prednisone have been identified and are guiding the selection of individual dosage rates. As an alternative, a single timed concentration can determine an apparent value for prednisone clearance from which an individual dosage can be calculated. In contrast, numerous sources of inter- and intraindividual variability in cyclosporin pharmacokinetics prevent the easy selection of safe and effective starting dose rates. Indeed, test doses of cyclosporin followed by series of blood samples and the calculation of individual pharmacokinetic parameters are needed to assure successful immunosuppression right from the start. Furthermore, only continued monitoring sustains immunotherapy vis-à-vis intraindividual variability and a narrow therapeutic range of cyclosporin concentrations.

The non-linear pharmacokinetics of prednisone and prednisolone. III. Experiments using the rabbit as an animal model.

Intravenous zero order infusions were administered to New Zealand white rabbits. In a pilot study using one rabbit, prednisone and prednisolone clearance values increased with increase in either prednisone or prednisolone infusion rates. In the second study, prednisone was infused until both prednisone and prednisolone achieved steady-state concentrations. In the third study, prednisone was infused until only prednisone achieved steady-state concentrations. The results of the three experiments support the use of a non-linear reversible metabolism model to describe the pharmacokinetic relationship between prednisone and prednisolone.

The nonlinear pharmacokinetics of prednisone and prednisolone. II. Plasma protein binding of prednisone and prednisolone in rabbit and human plasma.

The protein binding characteristics of prednisone and prednisolone were determined in human and rabbit plasma and in a 4.7 per cent human serum albumin (HSA) solution. The influence of prednisolone on prednisone binding in human plasma was also examined. Prednisolone exhibited nonlinear binding and prednisone linear binding characteristics in both human and rabbit plasma. Prednisone binding was not influenced by the presence of prednisolone. Prednisone binding to HSA was linear but to a degree substantially lower than observed in human plasma, suggesting the possibility that prednisone binds to other proteins in human plasma. The results support the hypothesis that the protein binding characteristics of prednisone and prednisolone do not explain the reported nonlinear pharmacokinetics of prednisone.

The non-linear pharmacokinetics of prednisone and prednisolone. I. Theoretical.

Three simple linear and three simple non-linear pharmacokinetic models are presented which incorporate the reversible metabolism that occurs between prednisone and prednisolone. Under steady-state conditions it is possible to not only distinguish between the linear and non-linear models but also to determine which particular model of each group applies to a given set of data. While the non-linear conversion of prednisolone to prednisone is important in explaining the pharmacokinetics of prednisone in all three non-linear models, the same is not true for prednisolone.

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.

Pharmacokinetics of prednisone and its metabolite prednisolone in children with nephrotic syndrome during the active phase and in remission.

The kinetics at steady state of prednisone and its metabolite prednisolone were determined in nine nephrotic children during the active phase of the disease and in remission. There were no differences in serum prednisone levels between the two occasions. Prednisone levels were lower than prednisolone levels. Total serum prednisolone levels were significantly lower during the active phase than in remission (AUC: 2452 +/- 207 vs 3392 +/- 293 ng ml-1 h respectively). Half-life values were similar on both occasions. The binding of prednisolone to serum proteins was markedly impaired during the active phase as compared to the remission. Free fraction values correlated positively with total drug concentration. A negative correlation between free fraction and serum albumin level was found during the active phase. Free prednisolone levels during the active phase did not differ significantly from those observed during remission (AUC: 937 +/- 128 vs 847 +/- 81 ng ml-1 h respectively). These data indicate that pharmacokinetic changes are unlikely to be responsible for alterations in steroid responsiveness in nephrotic patients with hypoalbuminaemia.

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 400 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 5 mg 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.

Proceedings of the Australian Society for Medical Research.

Proceedings of the Australian Society for Medical Research.