Disposition and biotransformation of the antipsychotic agent olanzapine in humans.

Disposition and biotransformation of the new antipsychotic agent olanzapine (OLZ) were studied in six male healthy volunteers after a single oral dose of 12.5 mg containing 100 microCi of [14C]OLZ. Biological fluids were analyzed for total radioactivity, the parent compound (GC/MS), and metabolites (electrospray LC/MS and LC/MS/MS). Mean radiocarbon recovery was approximately 87%, with 30% appearing in the faces and 57% excreted in the urine. Approximately half of the radiocarbon was excreted within 3 days, whereas > 70% of the dose was recovered within 7 days of dosing. Circulating radio-activity was mostly restricted to the plasma compartment of blood. Mean peak plasma concentration of OLZ was 11 ng/ml, whereas that of radioactivity was 39 ng eq/ml. Mean plasma terminal elimination half-lives were 27 and 59 hr, respectively, for OLZ and total radioactivity. With the help of NMR and MS data, a major metabolite of OLZ in humans was characterized as a novel tertiary N-glucuronide in which the glucuronic acid moiety is attached to the nitrogen at position 10 of the benzodiazepine ring. Another N-glucuronide was detected in urine and identified as the quaternary N-linked 4'-N-glucuronide. Oxidative metabolism on the allylic methyl group resulted in 2-hydroxymethyl and 2-carboxylic acid derivatives of OLZ. The methyl piperazine moiety was also subject to oxidative attack, giving rise to the N-oxide and N-deemethyl metabolites. Other metabolites, including the N-deemethyl-2-carboxy derivative, resulted from metabolic reactions at both the 4' nitrogen and 2-methyl groups. The 10-N-glucuronide and OLZ were the two most abundant urinary components, accounting for approximately 13% and 7% of the dose, respectively. In fecal extracts, the only significant radioactive HPLC peaks were due to 10-N-glucuronide and OLZ representing, respectively, approximately 8% and 2% of the administered dose. Semiquantitative data obtained from plasma samples from subjects given [14C]OLZ suggest that the main circulating metabolite is 10-N-glucuronide. Thus, OLZ was extensively metabolized in humans via N-glucuronidation, allylic hydroxylation, N-oxidation, N-dealkylation and a combination thereof. The 10-N-glucuronidation pathway was the most important pathway both in terms of contribution to drug-related circulating species and as an excretory product in feces and urine.

Disposition of the monoclonal antibody-vinca alkaloid conjugate, KS1/4-DAVLB (LY256787), in Fischer 344 rats and rhesus monkeys.

The conjugate, KS1/4-DAVLB, of the murine monoclonal antibody KS1/4 with the vinca alkaloid 4-desacetylvinblastine (DAVLB) was administered intravenously to rats and monkeys. Terminal plasma half-life (t1/2) values were measured as radioequivalents and as functionally immunoreactive antibody conjugate after dosing with KS1/4-[3H]DAVLB. The t1/2 values, determined radiometrically, were 145 hr and 62 hr in male rats after 10 and 100 mg/kg doses and 92 hr and 90 hr in male and female monkeys after a 40 mg/kg dose. Comparable results were obtained when the functionally immunoreactive conjugate concentrations were determined by an enzyme-linked immunosorbent assay technique. The ratio of 35S:3H in the plasma after dosing rats with 100 mg/kg [35S]KS 1/4-[3H]DAVLB remained reasonably constant during 336 hr. Less than 1% of the total vinca alkaloid equivalents present in the plasma at any time could be extracted as free vinca species; the major vinca alkaloid metabolities present at early time points were hemisuccinate derivatives of DAVLB, whereas, at later times, DAVLB and its N-oxide were equally as concentrated. The major pathway of elimination was fecal with about one-half of the administered radioactivity cleared in 150-250 hr. After dosing with [35S]KS 1/4-[3H]DAVLB, the ratio of 35S:3H radioactivity in the bile was substantially less than that in the plasma. Evaluation of radioactivity eluted from the bile by size-exclusion HPLC showed that almost all of the tritium was associated with material of lower molecular weight than that of KS 1/4-DAVLB.(ABSTRACT TRUNCATED AT 250 WORDS)

Disposition of the monoclonal antibody-vinca alkaloid conjugate KS1/4-DAVLB (LY256787) and free 4-desacetylvinblastine in tumor-bearing nude mice.

The monoclonal antibody-vinca alkaloid conjugate, KS1/4-DAVLB (LY256787), and free 4-desacetylvinblastine (DAVLB) were administered i.v. to male athymic nude mice bearing P3/UCLA human lung adenocarcinoma tumors. Although the plasma pharmacokinetics were similar between LY256787 and DAVLB (terminal plasma half-lives of 62 and 83 hr, respectively), substantial differences in the volumes of distribution and initial redistribution-elimination phases were found. Uptake of LY256787 into tumor was apparent, with maximal radioequivalent concentrations measured 96 hr after dosing; no similar uptake was found after dosing with free DAVLB. The ratios of concentrations of drug radioequivalents in tumor to those in other tissues were generally greater than 1.0 when measured 24 to 48 hr after dosing with LY256787 but were less than 1.0 after free DAVLB. These data support the concept of site-specific delivery to the tumor tissue of the vinca alkaloid by the antibody. Plasma pharmacokinetics and tissue distribution were compared in males and females with a lower dose of LY256787. No sex-related differences in the plasma pharmacokinetics were found (terminal half-lives of 90 and 84 hr in males and females). Some sex-related biodistribution differences occurred. In all studies, the primary route of elimination was fecal. These studies suggest that the KS1/4 monoclonal antibody targets DAVLB to the P3/UCLA human lung adenocarcinoma in vivo in the human xenograft model and that an increased therapeutic index may be achieved with LY256787 over conventional free drug therapy.

Dapsone-induced jaundice.

Enthusiasm in the use of dapsome for acne conglobata and other severe acne has created an increase in the use of this drug by dermatologists. We describe three patients in whom jaundice developed during dapsome therapy of 3 to 36 weeks' duration. Jaundice was due to cholestasis in two cases and to hemolysis in the third. These significant side effects call for careful observation by the physician if dapsone is to be used with safety.

Do polyunsaturated fats predispose to malignant melonoma?

The consumption of polyunsaturated fats of patients with malignant melanoma and of a control group of patients with benign naevi has been compared in order to determine whether polyunsaturated fats predispose to the development of malignant melanoma. Patients with malignant melanoma had not consumed excessive quantities of polyunsaturated fats. Thus, there was no evidence to indicate that ingestion of polyunsaturated fats is associated with an increase in incidence of melanoma.