The bioavailability of phenytoin from ACC-9653 versus intravenously administered sodium phenytoin was determined using a crossover design for intravenous and intramuscular administration of ACC-9653 to healthy volunteers. Absolute bioavailability of phenytoin derived from ACC-9653 in each subject was calculated as the ratio of the phenytoin area under the plasma concentration time curve for time 0 to infinity [AUC(0-inf)] after ACC-9653 divided by the phenytoin AUC(0-inf) after intravenous sodium phenytoin. The mean absolute bioavailability of ACC-9653 was 0.992 after intravenous administration and 1.012 after intramuscular administration. These data establish that the bioavailability of ACC-9653 is complete following intravenous or intramuscular administration in single-dose volunteer studies. The absolute bioavailability of phenytoin derived from ACC-9653 in subjects with therapeutic plasma phenytoin concentrations is being studied in patients given simultaneous infusions of stable isotope-labeled tracer doses of ACC-0653 and sodium phenytoin.

Thirteen HLA-identical bone marrow donors served as the sole source of daily granulocyte transfusions for respective marrow recipients during the period of severe neutropenia between transplantation and engraftment. They experienced 12 to 29 (median, 17) daily, continuous flow centrifugation leukapheresis procedures using hydroxyethyl starch, but no corticosteroids, with little serious difficulty. No immediate clinical reactions occurred in 90 percent of 228 procedures. Mild citrate reactions were noted in 9 percent, and only two procedures (0.8%) were discontinued due to severe reactions. Ten donors (77%) answered a questionnaire mailed weeks later, and six reported transient, late clinical adverse effects. Five had moderate dermatologic problems; one had minimal hypertension requiring no therapy. Donors were monitored daily for laboratory abnormalities while donating granulocytes. Hemoglobin concentration and platelet counts remained stable (autologous red cell transfusions had been given). Blood leukocyte counts gradually fell (p less than 0.05), particularly after 10 or more daily granulocyte donations, and this fall was associated with a decrease of about 33 percent in leukocyte yields. No attempts were made to improve yields by giving higher doses of hydroxyethyl starch or by corticosteroid stimulation. With primary emphasis on donor safety, it seems feasible for a few compatible donors to provide prolonged granulocyte transfusion support for designated patients. However, diminishing leukocyte yields may result from intensive, repeated leukapheresis.

Measurement of the absolute bioavailability of phenytoin (PHT) derived from test doses of phenytoin prodrug (PPD) at therapeutic PHT serum concentrations is complicated by two problems: 1) the area under the serum concentration versus time curve (AUC) produced by a given size of test dose will vary directly with background PHT serum concentration due to the nonlinear pharmacokinetic properties of PHT; 2) PPD is more water soluble than PHT, making renal excretion of PPD more likely. The authors describe a double-stable isotope method that obviates these two problems. Using only six subjects, the authors were able to demonstrate bioequivalence of PHT derived from intravenous PPD with intravenous PHT by current FDA standards for AUC ratio of test/reference formulation (90% confidence intervals between 0.80 and 1.20; ratio > or = 0.80 in > or = 80% of subjects; statistical power to detect a difference of 0.20 with a probability of 0.80).

The pharmacokinetics of moricizine and two of its metabolites, moricizine sulfoxide and phenothiazine-2-carbamic acid ethyl ester sulfoxide, were studied in healthy control subjects and in patients with chronic liver disease (cirrhosis). Moricizine disposition was significantly altered by hepatic cirrhosis. Compared to healthy subjects, the hepatic disease patients had an increased Cmax (59%), an increased t1/2 (141%), and a reduced plasma clearance (71%). Additionally, small but statistically significant increases were observed for tmax and the fraction of moricizine not bound to plasma proteins in patients with hepatic disease. The elimination of both moricizine metabolites was also altered by hepatic dysfunction as indicated by significantly prolonged terminal half-lives. Furthermore, there was a reduction in the conversion of moricizine to moricizine sulfoxide. Both hepatic blood flow and hepatic metabolizing capacity were assessed in all subjects and patients by administration of indocyanine green and antipyrine, respectively. Indocyanine green and antipyrine plasma clearances were decreased by 38 and 51%, respectively, indicating that both functions were diminished by hepatic cirrhosis. We conclude that the moricizine dose required for arrhythmia patients with hepatic disease should be lower, and perhaps, the dosing frequency should be less than in patients with normal liver function.

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