Effect of food on the absorption and pharmacokinetics of prednisolone from enteric-coated tablets

Summary We have studied the influence of food and dose (50, 100, 200 mg) on the oral systemic availability of the broad spectrum antifungal itraconazole and the pharmacokinetics after repeated dosing of 100 mg in six healthy volunteers.The relative systemic availability of itraconazole capsules compared with solution averaged 39.8% in the fasting state but 102% in the post-prandial state. Food did not significantly affect the t_max of the capsules. Itraconazole AUC at single doses of 50, 100, and 200 mg had a ratio of 0.3:1:2.7, and the steady-state AUC (0–24) after 15 days of 100 mg was five times the single-dose AUC.These findings suggest non-linear itraconazole pharmacokinetics in the range of therapeutically used doses. Furthermore, capsules should be given shortly after a meal to ensure optimal oral systemic availability.     

Pharmacokinetics of intravenous and oral prednisolone.

1 Doses of 16, 32, 48 and 64 mg prednisolone were administered intravenously to normal volunteers who also received 100 prednisolone orally. Plasma prednisolone concentrations were estimated by quantitative thin layer chromatography. 2 The bioavailability fraction was 1.063 +/- 0.154 (s.d.) indicating complete availability of prednisolone following oral administration. 3 The mean T 1/2 over all doses were 4.11 +/- 0.97 (s.d.) h and there was no evidence of a dose-related change in its value. 4 The mean systemic clearance over all doses was 0.104 +/- 0.034 (s.d) 1 h-1 kg-1. There was no evidence of a dose-related change in clearance or in the apparent volume of distribution (overall mean 0.588 +/- 0.152 1 kg-1). 5 The area under the plasma concentration-time curve was linearly related to dose. 6 Plasma concentration-time curves normalised for dose were superimposable. 7 It was concluded that over the dose range investigated, non-linear pharmacokinetic behaviour had not been demonstrated in this group of normal volunteers.     

Efflux of Zidovudine and 2′,3′-Dideoxyinosine Out of the Cerebrospinal Fluid When Administered Alone and in Combination to Macaca nemestrina

To determine if there is active efflux of zidovudine (ZDV) and 2,3-dideoxyinosine (ddl) out of the cerebrospinal fluid (CSF), and if this efflux is saturable, we investigated the steady-state CSF/plasma concentration ratio of the two drugs when administered alone or in combination. Constant-rate infusions of ZDV, ddl or both were administered to seven macaques (Macaca nemestrina) through a chronic venous catheter for a minimum of 28 hr. Antipyrine, a marker of passive diffusion, was coinfused in all experiments. Blood (5 mL) and CSF samples (0.5–1 mL) were collected by venous and lumbar/thoracic punctures, respectively, at 24 and 28 hr after beginning the infusion. When ZDV and ddl were administered alone, the steady-state CSF/plasma concentration ratios were significantly different from unity (ZDV, 0.20 ± 0.08; ddI, 0.09 ± 0.04) and were independent of the plasma concentration (P > 0.05). In contrast, the CSF/plasma concentration ratio of antipyrine (0.82 ± 0.19) was close but significantly smaller than unity (P > 0.05). The CSF/ plasma concentration ratios after simultaneous administration of ZDV and ddI were not significantly different (P > 0.05) from those obtained after administration of the drugs alone. These results suggest that ZDV and ddI are actively transported out of the CSF; however, within the concentration range studied, this efflux is neither saturable nor mutually competitive. Concomitant administration of ZDV and ddI did not produce a systemic interaction in the animals, indicating that the pharmacokinetics of either drug is unaffected by the presence of the other.     

Interaction of Zidovudine (Azidothymidine) with Isoprinosine and Probenecid in Macaca fascicularis

Pharmaceutical Research -     

Rifampicin reduces effectiveness and bioavailability of prednisolone

Rifampicin is an inducer of hepatic drug metabolising enzymes. This results in interactions with several drugs including oral anticoagulants, hypoglycaemics, and contraceptives. Concurrent treatment with prednisolone and rifampicin is given when tuberculosis coexists with a disease that is sensitive to steroids, when the diagnosis is uncertain, or occasionally in the treatment of severe tuberculosis. Two patients with respiratory disease were treated with both drugs: their condition improved considerably after rifampicin was withdrawn. Seven patients were then studied to assess the effect of rifampicin on the pharmacokinetics of prednisolone. Overall, rifampicin increased the plasma clearance of prednisolone by 45% and reduced the amount of drug available to the tissues (area under the plasma concentration time curve) by 66%. The effectiveness of prednisolone may be considerably reduced when rifampicin and prednisolone are used in combination.     

High-performance liquid chromatographic determination of prednisolone and its steroid 21-oate ester derivatives in rat plasma: pharmacokinetic applications

A high-performance liquid chromatographic (HPLC) technique was developed for the determination of prednisolone and its local anti-inflammatory steroid 21-oate ester derivatives in rat plasma. These new steroid esters (methyl 20 alpha- and 20 beta-dihydroprednisolonate; P4 alpha and P4 beta), developed for local use, were found to exhibit minimal systemic side effects as compared with prednisolone. The described method involves a simple organic extraction procedure and separation of steroids using a C18 reversed-phase column for pharmacokinetic study. The method allows simultaneous measurement of endogenous corticosterone following administration of P4 alpha, P4 beta, and prednisolone. The calibration curves of the steroids were linear over a wide range of concentrations (0.05 to 10 micrograms/mL). The limit of detection of the assay for all tested steroids is 10-20 ng/mL. The method is reproducible, with a coefficient of variation of less than 10% for all steroids over a wide range of concentrations. No interference from endogenous steroids nor exogenous steroids was found. The presented method is simple, rapid, specific, sensitive, and reproducible.     

Methylprednisolone pharmacokinetics after intravenous and oral administration.

1. The pharmacokinetics of methylprednisolone (MP) were studied in five normal subjects following intravenous doses of 20, 40 and 80 mg methylprednisolone sodium succinate (MPSS) and an oral dose of 20 mg methylprednisolone as 4 x 5 mg tablets. Plasma concentrations of MP and MPSS were measured by both high performance thin layer (h.p.t.l.c.) and high pressure liquid chromatography (h.p.l.c.). 2. The mean values (+/- s.d.) of half-life, mean residence time (MRT), systemic clearance (CL) and volume of distribution at steady state (Vss) of MP following intravenous administration were 1.93 +/- 0.35 h, 3.50 +/- 1.01 h, 0.45 +/- 0.12 lh-1 kg-1 and 1.5 +/- 0.63 1 kg-1, respectively. There was no evidence of dose-related changes in these values. The plasma MP concentration-time curves were superimposable when normalized for dose. 3. The bioavailability of methylprednisolone from the 20 mg tablet was 0.82 +/- 0.11 (s.d.). 4. In vivo hydrolysis of MPSS was rapid with a half-life of 4.14 +/- 1.62 (s.d.) min, and was independent of dose. In contrast, in vitro hydrolysis in plasma, whole blood and red blood cells was slow; the process continuing for more than 7 days. Sodium fluoride did not prevent the hydrolysis of MPSS.