Inhibition of N-nitrosodimethylamine metabolism in rats by ether anesthesia.

Short-term exposure to diethyl ether strongly inhibits the metabolism of N-nitrosodimethylamine (NDMA). Twenty-six 6-week-old male Fischer 344 rats were exposed to ether vapor until their righting reflex was lost (approximately 2 min). The animals were removed from the ether and NDMA was immediately administered by i.v. bolus injection at a dose of 300 microgram/kg via a cannula surgically inserted 20 h earlier. A second group of 28 rats received injections of NDMA in an identical manner but without ether exposure. In the unanesthetized animals blood levels of NDMA declined with a half-life of 11 min; by contrast essentially constant blood levels of NDMA were observed in ether-treated animals for 120 min after removal from the anesthetic. The apparent total systemic clearance for the 5-h experiment was reduced from 43 ml/min/kg without ether to 5 ml/min/kg with ether. Diethyl ether has been found previously to inhibit the metabolism of other drugs requiring oxidative metabolism but the suppression of clearance documented here appears to be unusually pronounced. It is recommended that ether's potential for altering metabolic rates be carefully considered when planning or interpreting animal experiments.

Low-dose in vivo pharmacokinetic and deuterium isotope effect studies of N-nitrosodimethylamine in rats.

The rates of elimination of N-nitrosodimethylamine (NDMA) and its fully deuterated analogue (N-nitrosodi[2H6]methylamine, [2H6]NDMA) were studied in vivo to explore the origins of the difference in their carcinogenicity. Male Fischer 344 rats, 7.5 weeks of age, were given nitrosamine bolus doses of 1.35 mumol/kg by tail vein injection and 2.02 or 4.05 mumol/kg by p.o. gavage. Animals were sacrificed at various time points from 2.5 to 180 min after i.v. administration or 5 to 120 min after p.o. dosage, and their blood was analyzed for NDMA by gas chromatography-high resolution mass spectrometry. After i.v. injection, blood nitrosamine concentrations declined in an apparently biexponential manner with a terminal half-life of 10 min for NDMA and 12 min for [2H6]NDMA. The apparent total systemic blood clearances for NDMA and [2H6]NDMA were 39 and 26 ml/min/kg, respectively. The apparent steady-state volumes of distribution were nearly identical (297 and 309 ml/kg, respectively). The areas under the curve after 2.02- and 4.05-mumol/kg p.o. doses were proportional to dose. The apparent bioavailability of NDMA was 8%, while that of [2H6]NDMA was 21%. Isotope effects calculated as the ratios of first-pass metabolism, total systemic clearances, bioavailabilities, and intrinsic hepatic clearances were 1.2, 1.5, 2.6, and 3.2, respectively. The isotope effect determined from blood concentrations measured after simultaneous administration of NDMA and [2H6]NDMA by steady-state infusion (each at 1.5 mumol/kg/h) was 2.6 +/- 0.9 (SD). This study thus provides quantitative reference data on the time course of the disappearance of both N-nitrosodimethylamine and its deuterated analogue from blood (over 5 to 8 half-lives) after doses similar to those used to elicit liver tumors in chronic feeding studies, confirms the first-pass effect on their metabolism using direct blood measurements, and permits estimation of their bioavailabilities from actual blood concentrations. The results suggest that elimination pathways not involving alpha-hydroxylation are more important than is currently recognized.

Pharmacokinetics of teceleukin (recombinant human interleukin-2) after intravenous or subcutaneous administration to patients with cancer.

Single doses of teceleukin ranging from 0.1 to 30 x 10(6) units were administered to cancer patients as intravenous infusions or subcutaneous injections. Serum samples were analyzed using a bioassay. In general, teceleukin was rapidly eliminated after intravenous administration, with half-lives ranging from 0.24 to 3.3 h. Teceleukin disappeared from serum more slowly following subcutaneous administration, with half-lives of 2.7 to 12.2 h. This finding may be a result of slow absorption from the subcutaneous injection site. Serum concentrations of teceleukin increased in an apparently dose-proportional manner following intravenous administration. When administered subcutaneously, serum concentrations increased with increasing dose but in a manner that was less than dose-proportional, possibly due to dose-dependent bioavailability for subcutaneously administered teceleukin.

Quantification of recombinant interleukin-2 in human serum by a specific immunobioassay.

A sensitive and specific assay for recombinant interleukin-2 (rIL-2) in human serum is described. The assay is based on a sequential sandwich immunobioassay that uses a microtiter plate coated with anti-rIL-2 monoclonal antibody (specific for recombinant human IL-2) to capture rIL-2 from serum, and an IL-2 dependent T-cell line that proliferates in a dose-dependent fashion. The lower limit of quantitation of the assay is 2 units/mL (1 unit = approximately 50 pg) using 0.1 mL of serum and the calibration curves ranged from 2 to 50 units/mL. Data are reported on the sensitivity, precision, reproducibility, and specificity of the assay; the stability of rIL-2 in serum; and the recovery of rIL-2 from serum. We also report on the use of the procedure to assay clinical samples from patients with AIDS undergoing treatment with rIL-2.