Pilot study of the pharmacokinetics of methylprednisolone after single and multiple intravenous doses of methylprednisolone sodium succinate and methylprednisolone suleptanate to healthy volunteers.

The pharmacokinetics of methylprednisolone were evaluated in 29 healthy volunteers after multiple intravenous doses of methylprednisolone sodium succinate or the novel prodrug, methylprednisolone suleptanate. Subjects were assigned randomly to one of four treatment groups (40, 100, 250, or 500 mg) and then randomly assigned to receive either the sodium succinate or suleptanate prodrugs. Doses were administered every 6 hours for 48 hours. Plasma and urine were assayed for methylprednisolone and unchanged prodrug using HPLC methods. Methylprednisolone pharmacokinetics exhibited both a dose and time dependency, which was similar for administration of both prodrugs. After first-dose administration, mean clearance increased from 19.5 L/hr for 40-mg doses to 27.7 L/hr after 500-mg doses of the sodium succinate ester, and from 20.1 to 31.7 L/hr after the suleptanate ester. After multiple dosing, mean clearance values increased from 31.1 to 44.7 L/hr for sodium succinate dosing, and from 31.5 to 46.0 L/hr for suleptanate dosing. Apparent systemic clearance values determined after multiple dosing were 1.5- to 1.8-fold greater than corresponding first-dose values. No dependence on time was apparent for any prodrug pharmacokinetic parameter. These data suggest that the dose dependency of methylprednisolone pharmacokinetics is related to dose-dependent prodrug hydrolysis, whereas the time dependence possibly reflects auto-induction of methylprednisolone metabolism. Based on comparison of methylprednisolone pharmacokinetic parameters derived for each prodrug, methylprednisolone suleptanate resulted in a faster and slightly more efficient conversion to methylprednisolone than methylprednisolone sodium succinate.

Absence of effect of food on alprazolam absorption from sustained release tablets.

This study examined the effect of food on alprazolam absorption from a mixed polymeric matrix sustained release (SR) tablet in 21 healthy adults. Each subject received each of three treatments according to a crossover design: 1 mg alprazolam SR tablet while fasting; 1 mg alprazolam SR tablet immediately after a standardized breakfast; 1 mg alprazolam conventional tablet while fasting. The breakfast contained approximately 33 g protein, 55 g fat, and 58 g carbohydrate (850 calories). Serial blood samples were obtained and plasma alprazolam levels determined by HPLC. Results indicate that the SR tablet was minimally affected by food. Relative bioavailabilities of the SR tablet while fasting and with food were 100 per cent and 97 per cent, respectively. Although statistically significant, differences in mean Cmax values between SR tablets administered with and without food were small (12 per cent increase with food). Rates of absorption as measured by mean tmax values were also nearly the same: 7.2 h while fasting and 7.0 h with food. Absorption was relatively uniform with the SR tablets. Coefficients of variation for Cmax, tmax, and AUC were somewhat smaller with the SR tablet than with the conventional tablet.

Absorption kinetics of rectally and orally administered ibuprofen.

The bioavailability of rectally administered sodium ibuprofen solution and aluminum ibuprofen suspension was determined in eight normal subjects relative to the same treatments administered orally. The results indicate that the suspension was less bioavailable than the solution irrespective of the route of administration. Although not bioequivalent, rectally administered ibuprofen solution compared favourably with orally administered ibuprofen solution. The mean AUC and Cmax from rectal administration were 87 per cent and 62 per cent of the corresponding values achieved after oral administration. Mean residence times and peak times were 1-3 h longer with the rectal solution, indicating a slower rate of absorption. Absorption after rectal administration was zero order in some subjects while absorption after oral administration was first order. This may be due to the large differences in surface area between absorption sites. Since sodium ibuprofen solution is absorbed when given rectally, this route of administration could be used in patients unable to take oral ibuprofen.

Absorption of minoxidil after topical application: effect of frequency and site of application.

The effect of application site and frequency on the systemic absorption of topical minoxidil was studied in 52 normal men. Subjects received 1 ml 3% minoxidil solution applied four, six, or eight times daily to the scalp or two, four, six, or eight times daily to the chest for 14 days. Serum and urine were collected and analyzed for minoxidil. No systemic minoxidil accumulation occurred from increasing application frequency to the scalp. Trends in the chest data suggest that absorption may have been lower with the twice-daily regimen. Absorption through the scalp and chest were similar for the lower-frequency regimens; however, trends in the eight-times-a-day regimens suggest that absorption may have been somewhat greater from application to the scalp. Systemic minoxidil accumulation resulting from frequent application is unlikely. The initial dose probably saturates the skin for a period of time longer than the dosing intervals examined.

The formation of a thrombin-like material (TLM) following stimulation of leukocytes.

When thrombin, tissue thromboplastin or Russell's viper venom was added to a suspension of either lymphocytes or neutrophils containing normal plasma, aggregation of these cells ensued. The aggregate formed one gelatinous mass which was readily separable from the cell free supernatant, an aliquot of which caused platelet aggregation. This leukocyte derived platelet aggregatory substance had characteristics similar to thrombin but not AGEPC. When plasma deficient in Factor V was substituted for normal plasma, the platelet stimulatory substance was not produced. Substitution with plasma deficient in Factor VII, VIII, IX, X or XI was without effect. Thrombin clotting time measurements indicated a generation of activity, relative to thrombin, of about 3.0 U/5 X 10(6) cells.