Comparative bioavailability: Eight commercial prednisone tablets

Abstract

Two four-treatment crossover bioavailability studies were performed in panels of 12 adult male volunteers with eight different commercial prednisone tablets. Plasma samples from the first study were assayed by radioimmunoassay for both prednisone and prednisolone. Plasma samples from the second study were assayed for prednisolone only. Statistical analyses of the data showed significant differences in the rate of appearance of prednisolone in plasma, but not in the amount converted to prednisolone. Some observations are made on the relationships between prednisone and prednisolone concentrations in plasma following oral ~lministration of prednisone.KEY WORDS: prednisone bioavailability; elimination half-lives of prednisone and prednisolone; prednisone and prednisolone plasma levels following prednisone. INTRODUCTIONWith the development of radioimmunoassays for prednisone (1) and its metabolite, prednisolone (2), it is now possible to measure the plasma levels of these steroids following the oral administration of a single, low dose of prednisone. The early observations, of Campagna et al. Sullivan, Hallmark, Sakmar; Weidler, Earhart, and Wagner reported data on some prednisone tablets. One of these (6) reported results of our first prednisone study.It is well documented that prednisone is metabolized to prednisolone (7-9), which is assumed to be its active form. However, in most of these studies the metabolites of prednisolone have been isolated only from urine, or plasma levels of prednisolone have been measured following high doses of prednisone. In only one unpublished study of DiSanto et al. has the determination of both prednisone and prednisolone in plasma been undertaken.This article reports the results of two four-treatment crossover studies with commercially available prednisone tablets. In the second prednisone study both prednisone and prednisolone plasma levels were measured, while in the third prednisone study only prednisolone was measured in plasma. All tablets utilized in the studies were purchased on the open market by the Food and Drug Administration. EXPERIMENTAL In Vitro StudiesDissolution testing was performed in the laboratories of the Food and Drug Administration according to the specifications of the USP XVIII. Results of dissolution rate tests on the same tablets by another method will be reported in a subsequent publication. SubjectsTwelve adult male volunteers between the ages of 21 and 32 years, weighing between 60.3 and 82.6 kg and in good health, were selected for each study. Six of the subjects participated in both studies. Each subject received a medical history, physical examination, and blood and urine analysis including plasma 17-OHCS.All subjects selected received no barbiturates or other enzyme-inducing agents for a period of 30 days preceding the study until its completion. They received no other medication or alcoholic beverages for a period beginning 7 days preceding the study until completion of the study. The subjects were assigned numbers which were ordered according t...

Clinical Pharmacokinetics of Prednisone and Prednisolone

“…Gas-liquid chromatographic techniques have been used for prednisone (Pickup, 1973) and prednisolone (Bacon, 1969) estimations but lack the sensitivity required for determination in plasma following therapeutic doses, This criticism is true also of early attempts using spectrophotometry (Jenkins and Sampson, 1967;D'Arcy et al" 197 D, More sensitive competitive protein binding techniques (CPB) first developed by Murphy (1967) have been used for prednisolone estimations but lack specificity due to interference by endogenous corticosteroids, More recently published work has included a preliminary thin layer or paper chromatographic step to separate prednisolone from these endogenous steroids (English et al, 1974;Turner et al" 1973;Sandberg et al" 1970;Wilson et aI., 1975) or has made use of premedication with dexamethasone to suppress endogenous steroid production (Leclercq and Copinschi, 1974), The latter approach may, however, affect prednisolone pharmacokinetics by changing the transcortin binding capacity for the drug as a result ofthe lack of competition from endogenous cortisol (Angeli et aI., 1978), Radioimmunoassays (RIA) are commonly used for both prednisone (Colburn, 1974;Sullivan et aI., 1976;Schalm et al" 1976;Meikle et al" 1975) and prednisolone (Colburn and Buller, 1973;Sullivan et aI., 1974;Meikle et al" 1975;Schalm et al" 1976;Chakraborty et aI., 1976;Yotsumoto et al" 1974;Tembo et al" I 976a), Specificity problems have again been encountered due primarily to cross reactivity of prepared antisera with endogenous cortisone (prednisone assay) or cortisol (prednisolone assay), Cross reactivity has been reduced by dilution techniques (Colburn and Buller, 1975), by dexamethasone premedication (Sullivan et al" 1974(Sullivan et al" , 1975(Sullivan et al" , 1976, or by chromatography (Meikle et al" 1975), In terms of precision, the RIA (method of Sullivan et al" 1974) has been compared with a CPB method by Tembo et al, (1977a) and was shown to be inferior, Plasma from dexamethasone suppressed subjects was analysed, …”

“…Studies with prednisone have been restricted to relative bioavailability assessments, comparing areas under plasma prednisone (Sullivan et al, 1976) or prednisolone concentration-time curves (Sullivan et aI., 1975(Sullivan et aI., , 1976Di Santo and De Sante, 1975) following administration of various commercial prednisone preparations. The results indicated equivalent bioavailability but significant differences in drug absorption rate were observed, determined by the tablet dissolution rate.…”

Biowaiver Monographs for Immediate Release Solid OralDosage Forms: Prednisolone

“…[40], [41] Maximum serum concentrations occur within 1-2 h after administration of a single dose. [10], [11], [14], [31], [32], [35], [42][43][44] Food intake prolongs the time to peak concentration, but does not affect the extent of absorption. [45][46][47] No indication of existence of an absorption window was found in the literature.…”

Suppression of endogenous hydrocortisone with dexamethasone

“…One way to achieve this suppression is to administer dexamethasone. This procedure was used in studies on prednisone (10,11) and prednisolone (12,13). In these cases, dexamethasone administration was necessary since endogenous steroids cross react with the antiserums used in these radioimmunoassays.…”