In vitro metabolism of mifepristone (RU-486) in rat, monkey and human hepatic S9 fractions: identification of three new mifepristone metabolites.

1. In vitro metabolism of the antiprogestin drug mifepristone (RU-486) was studied after incubation with rat, monkey and human hepatic S9 fractions in the presence of an NADPH-generating system. 2. Unchanged mifepristone (approximately 45% of the sample(s) in rat; approximately 70% in monkey; approximately 65% in human) plus six metabolites, three known and three new, were profiled, quantified and tentatively identified on the basis of MS and MS/MS data. 3. The proposed metabolic pathways for mifepristone are proposed, and the two metabolic steps are (A) N-demethylation and (B) methyl oxidation. 4. Step A formed N-desmethyl mifepristone (M1) in major amounts (approximately 35% s in rat, 16% in monkey and human) and N,N-didesmethyl mifepristone (M2) in minor amounts (< 5% s in all species). Step B, or in conjunction with step A, produced four minor/trace metabolites, namely hydroxymethyl mifepristone (M3), hydroxymethyl M1 (M4), hydroxymethyl M2 (M5) and formyl mifepristone (M6).

Biotransformation of the antipsychotic agent, mazapertine, in dog--mass spectral characterization and identification of metabolites.

1. Biotransformation of the antipsychotic agent, mazapertine, was studied after a single oral administration of 14C-mazapertine succinate (10 mg/kg, free base) to six beagle dogs (three male, three female). 2. Following oral administration of 14C-mazapertine, plasma (0-48 h), urine (0-7 days), and faeces (0-7 days) were collected. Recoveries of total radioactivity in urine and faeces were 26.9 and 62.0% of the dose, respectively. 3. Unchanged mazapertine plus 14 metabolites were isolated and identified, which accounted for > 60% of the sample radioactivity in the plasma, 17% of the dose in urine and 28% of the dose in faecal extract. 4. Unchanged mazapertine accounted for < 4% of the radioactive dose in excreta samples and < 21% of the sample radioactivity present in plasma samples. 5. Seven metabolic pathways for the formation of metabolites were identified including: (1) phenyl hydroxylation, (2) piperidyl oxidation, (3) O-dealkylation, (4) N-dephenylation, (5) oxidative N-debenzylation, (6) depiperidylation and (7) conjugation. 6. Pathways 1, 2, 5 and 6 produced 4-OH-piperidyl, OH-phenyl-OH-piperidyl, carboxybenzoyl piperidine and depiperidyl analogues of mazapertine as major metabolites.

Ancillary approaches to toxicokinetic evaluations.

The principal objective of toxicokinetic studies is to assess systemic exposure of the toxicity species to test compound during nonclinical toxicity studies by generation of pharmacokinetic data on the rate, extent, and duration of exposure. Toxicokinetics are normally integrated within the toxicity studies (concomitant); however, there are a number of circumstances when prospective, retrospective, or other ancillary types of toxicokinetic studies are performed in support of toxicity studies. The need for retrospective toxicokinetic studies arises when the original toxicity study was conducted with insufficient plasma concentration determinations, especially when pilot toxicity studies show lack of toxicity or unusual organ toxicities. Examples of ancillary toxicokinetic studies from the Drug Metabolism and Drug Safety departments at The R. W. Johnson Pharmaceutical Research Institute and from the scientific literature are provided that highlight the challenges associated with these alternate approaches. Each example includes a discussion of the rationale for the supportive toxicokinetic study, the specific experimental designs, the data interpretation, and the usefulness of the toxicokinetic data in decision-making. The ancillary toxicokinetic studies cited provided important information on establishing systemic exposure during long-term toxicity studies, allowing comparisons to human exposures, elucidating compound-related toxicities, and explaining lack of toxicity due to autoinduction and resulting low levels of parent compound.

Pharmacokinetics and bioavailability of topiramate in the beagle dog.

Male and female beagle dogs showed rapid absorption following oral administration of single oral gavage (40 mg/kg) and single or multiple (15 days) oral capsule (10, 40, and 150 mg/kg) doses of the novel anticonvulsant drug, topiramate, with the peak plasma concentration (Cmax) occurring between 0.6 and 3.8 hr. The absolute bioavailability of an oral dose of topiramate was estimated to be in the range of 27-59%, depending on the formulation. The mean topiramate Cmax values increased in a dose-proportional manner for both single (9.2-137.7 micrograms/ml) and multiple (10.3-145.2 micrograms/ml) oral capsule administrations, whereas the corresponding area under the plasma concentration vs. time curve (AUC) values increased in a dose-related but nonproportional manner for both single (51-1131 micrograms.hr/ml) and multiple (54-858 micrograms.hr/ml) doses. Over the 10-150 mg/kg dosing range, oral plasma clearance and terminal half-life values were found to be 2.4-3.6 ml/min/kg and 2.6-3.7 hr following a single oral administration, and 3.0-4.2 ml/min/kg and 2.0-3.8 hr after multiple doses. There were no significant differences between the pharmacokinetic parameters calculated following the first and fifteenth daily doses of topiramate at the 10 and 40 mg/kg levels, indicating that there was no accumulation and no autoinduction or inhibition of enzymes that metabolize topiramate resulting from multiple dosing at these levels. A slight (24%) decrease in AUC was observed at the 150 mg/kg level after the fifteenth daily dose.(ABSTRACT TRUNCATED AT 250 WORDS)