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It is currently not clear whether the concentration-time curves of the immunosuppressants differ with respect to the CYP3A5, MDR1, or MRP2 genotype in dose-adapted stable kidney transplant patients. Dose/trough concentration ratios were obtained in 134 tacrolimus and 20 sirolimus-treated patients, and plasma concentration-time profiles were obtained from 16 (tacrolimus) and 10 (sirolimus) patients. Genotyping was carried out for CYP3A5 6986A>G; ABCB1 2677G>T/A, 3435C>T and ABCC2 -24C>T; 1249G>A; 3972C>T. Dose/trough concentration ratios were 0.67+/-0.3 and 1.36+/-0.73 x 10(3) l (P<0.00001) for tacrolimus and 0.42+/-0.17 and 0.84+/-0.46 x 10(3) l (P=0.18) for sirolimus in CYP3A5 non-expressors and expressors. The unadjusted tacrolimus area under curve (AUC)(0-12) was 106.8+/-17.5 ng/ml x h compared with 133.3+/-42.2 ng/ml x h (P=0.37) without affecting serum creatinine. Mean unadjusted AUC(0-24) of sirolimus did not differ significantly either. Therefore, CYP3A5 expressor status and not transporter variants is a main determinant of oral clearance, particularly for tacrolimus. Dose adaptation according to trough levels, however, appears to be sufficient to maintain similar concentration-time profiles.

To evaluate the effect of hyperthyroidism on the protein binding and metabolism of prednisolone, eight subjects with hyperthyroidism were investigated before and after thyroid status returned to normal. Hyperthyroidism was associated with a reduced volume of distribution of prednisolone, a decreased systemic availability of prednisolone after oral prednisone, a displacement of the prednisolone in equilibrium with prednisone equilibrium toward prednisone, and an increased nonrenal clearance of unbound prednisolone in the presence of an impaired 6 beta-hydroxyprednisolone formation. After oral prednisone or intravenous prednisolone, patients with hyperthyroidism had lower albumin-bound, transcortin-bound, and unbound concentrations of prednisolone but normal affinities of albumin and transcortin for prednisolone binding. These differences in prednisolone plasma concentrations were biologically relevant, because the capacity of these plasma samples to inhibit allogeneically stimulated lymphocytes was lower by 70% in the hyperthyroid than in the euthyroid state. Thus hyperthyroidism reduces the biologic effect of prednisolone and exhibits a differential effect on various enzymes involved in the catabolism of prednisolone.

Obesity is accompanied by altered secretion and disposition of sex and glucocorticoid hormones, including cortisol, and also confounds parameter normalization and drug dosage selection relative to body weight. Prednisolone disposition was assessed in eight obese and four normal male subjects after a dose of 33 mg iv. Steroid concentrations were determined by HPLC. Kinetics were related to ideal body weight (IBW) and total body weight (TBW). Uncorrected steady-state volume of distribution (Vss) of total prednisolone was 20% greater in obese subjects (36.7 and 44.1 l). This effect could be described by the relationship: Vss = 0.54 IBW + 0.09(TBW-IBW), with a distribution coefficient of 0.09 reflecting limited prednisolone uptake by fat. Protein binding parameters and albumin and transcortin concentrations were similar between groups. Uncorrected total and free prednisolone clearances (Cl) were increased in obesity (11.1 and 8.3 l/hr total; 65.4 and 46.5 l/hr free). Free prednisolone Cl correlated strongly (r = 0.80) with degree of obesity expressed as TBW/IBW. In the obese, endogenous cortisol concentrations were initially higher before exogenous steroid dosing, were suppressed at an identical rate, and returned to baseline more slowly than in normal subjects. The apparent hypersensitivity of the adrenal gland offsets the increased Cl of free prednisolone in obesity, indicating that weight-proportional dosage adjustments of this steroid in obesity should reflect TBW.

The effects of diphenylhydantoin (DPH) on the clearance of prednisolone from plasma, its bioavailability, and its biologic effectiveness were studied in 5 persons before and after daily DPH therapy for more than 3 wek. DPH decreased the mean half-time of disappearance of prednisolone from plasma by 45% and increased its metabolic clearance rate by an average of 77%. The gastrointestinal absorption of prednisolone and its first-pass clearance through splanchnic tissues were not significantly altered by DPH. The mean oral midnight dose of prednisolone required to suppress the 8 A.M. plasma level of cortisol to 5 microgram/dl was doubled following treatment of DPH. The increment in dose of prednisolone varied from 58% to 260% in the five individuals.

Prednisolone pharmacokinetics were compared in seven patients with asthma managed by alternate-day prednisone therapy and in seven patients with asthma requiring daily doses of prednisone. Steroid requirements of these patients were carefully characterized and had been stable for at least 12 months. Prednisolone volume of distribution, elimination clearance, and elimination t1/2 averaged 0.606 +/- 0.061 and 0.553 +/- 0.162 L/kg, 2.28 +/- 0.43 and 1.93 +/- 0.54 ml/min/kg, and 204 +/- 44 and 214 +/- 19 minutes in patients receiving alternate-day or daily prednisone therapy, respectively. These results indicate that differences in these pharmacokinetic parameters do not account for the well-established clinical observation that some patients require daily prednisone doses and that their disease cannot be managed with alternate-day steroid therapy.

The kinetics of prednisolone after intravenous prednisolone and oral prednisone were investigated in 19 young (23 to 34 years) and 12 elderly (65 to 89 years) subjects. The systemic availability of unbound prednisolone after oral prednisone and the apparent interconversion of prednisolone into prednisone and vice versa (reflecting the activity of the 11 beta-hydroxydehydrogenase) were independent of age. The total exposure of the elderly subjects to prednisolone was increased because the nonrenal (5.7 +/- 1.0 vs. 7.7 +/- 1.6 ml/min/kg, mean +/- SD; P less than 0.001) and renal (0.9 +/- 0.3 vs. 2.9 +/- 0.7 ml/min/kg; P less than 0.001) clearances of unbound prednisolone were lower in the elderly. The fractional clearance of 6 beta-hydroxyprednisolone (reflecting the activity of the 6 beta-hydroxylase) decreased linearly with the metabolic clearance of prednisolone. Despite increased prednisolone exposure, elderly subjects had higher endogenous cortisol concentrations. It was concluded that elderly subjects exhibit higher concentrations of both total and unbound prednisolone. Despite this greater exposure of target tissues, there appears to be less suppression of endogenous cortisol concentrations in plasma compared with younger subjects.

Plasma concentrations of free and total prednisolone were measured after oral doses at four time points to investigate the possibility of a diurnal variation in the drug's kinetics. There were marked differences in plasma prednisolone concentrations, clearance rates, and bioavailability of both free and total fractions at different times of the day. Changes in the protein binding characteristics of prednisolone with clock time resulted in marked differences between the kinetics of free and total prednisolone. It is recommended that for maximum efficacy and minimum toxicity prednisolone therapy be confined to once-daily dosing in the morning.

Six healthy women chronically (greater than 6 months) using oral contraceptives were age- and weight-matched with female controls. Each subject received prednisolone, 0.53 and 0.14 mg/kg iv. In the subjects taking oral contraceptives there were significant decreases in total clearance, unbound clearance, and volume of distribution at steady state for total drug, and significant increases in total and unbound prednisolone t1/2 and hydrocortisone concentrations compared with control subjects at both the high and low prednisolone doses. Both the oral contraceptive group and the control group had significantly higher total clearance, volume of distribution for total drug, and unbound fraction for the high dose compared with the low dose. Data suggest that chronic low-dose contraceptive steroid use results in a marked decrease in prednisolone clearance; however, dose-dependent changes in kinetics are still observed.

Prednisone is a glucocorticoid that must be converted in vivo to prednisolone for pharmacologic activity. We examined the effects of the H2-receptor antagonists cimetidine and ranitidine on the time course of plasma prednisolone concentrations after an oral dose of prednisone. Nine healthy men received each of three oral treatments in a double-blind, balanced, crossover manner: cimetidine (300 mg every 6 hours), ranitidine (150 mg twice a day), or placebo for 4 days, with prednisone (40 mg) taken also on day 4. Serial blood and urine samples were collected for 30 hours after prednisone dosing. Prednisone and prednisolone plasma and urine concentrations were analyzed by HPLC. No differences were found between treatments in the maximum prednisolone plasma concentration, t1/2, apparent volume of distribution, and AUC. Cimetidine reduced the mean (+/- SD) ratio of prednisone dose to the plasma prednisolone AUC (16.6 +/- 2.9 L/hr) below that ratio after ranitidine (19.2 +/- 4.2 L/hr) and placebo (19.3 +/- 2.8 L/hr), and resulted in the lowest fractional excretion of prednisolone in the urine (5.2% +/- 2.2%, 9.8% +/- 4.5%, and 12.4% +/- 4.9%, respectively). The minor alterations in prednisolone kinetics during concomitant cimetidine dosing are not likely to induce clinically significant alterations in steroid effect.