Increased human immunodeficiency virus type 1 replication in human peripheral blood mononuclear cells induced by ethanol: potential immunopathogenic mechanisms.

Previous studies have shown that alcohol ingestion significantly increases human immunodeficiency virus type 1 (HIV-1) replication in peripheral blood mononuclear cells (PBMC) isolated and infected with HIV-1 in vitro. Whether the increased replication of HIV-1 observed after alcohol ingestion was due to unknown factors released from the gastrointestinal tract during alcohol ingestion or to certain metabolites produced by intestinal flora that degraded alcohol was investigated. In addition, cellular mechanisms involved in the increased replication of HIV-1 after alcohol exposure were evaluated. Twelve healthy HIV-1-seronegative subjects abstained from alcoholic beverages for >10 days. Nine were infused with 500 mg/kg ethanol (7.5% at 20 ml/kg/h) in saline, whereas 3 were infused with saline alone. Compared with saline-infused subjects, ethanol-infused subjects' PBMC exhibited significantly increased replication of HIV-1 when infected in vitro, which was associated with increased inhibition of CD8+ T lymphocytes' function by alcohol.

Alteration of etoposide pharmacokinetics and pharmacodynamics by cyclosporine in a phase I trial to modulate multidrug resistance.

PURPOSE: To determine the effects of high-dose cyclosporine (CsA) infusion on the pharmacokinetics of etoposide in patients with cancer. PATIENTS AND METHODS: Sixteen patients were administered 20 paired courses of etoposide and CsA/etoposide. Etoposide was administered daily for three days, alone or with CsA, which was delivered by a loading dose and 3-day infusion. Etoposide was measured by high-performance liquid chromatography (HPLC) and serum CsA by nonspecific immunoassay. Etoposide pharmacokinetics included area under the concentration-time curve (AUC), total and renal clearance (CL), half-life (T1/2), and volume of distribution at steady state (Vss). RESULTS: CsA concentrations more than 2,000 ng/mL produced an increase in etoposide AUC of 80% (P less than .001), a 38% decrease in total CL (P < .01), a > twofold increase in T1/2 (P < .01), and a 46% larger Vss (P = .01) compared with etoposide alone. CsA levels ranged from 297 to 5,073 ng/mL. Higher CsA levels (< 2,000 ng/mL v > 2,000 ng/mL) resulted in greater changes in etoposide kinetics: Vss (1.4% v 46%) and T1/2 (40% v 108%). CsA produced a 38% decrease in renal and a 52% decrease in nonrenal CL of etoposide. Etoposide with CsA levels > 2,000 ng/mL produced a lower WBC count nadir (900/mm3 v 1,600/mm3) compared with baseline etoposide cycles. CONCLUSIONS: High-dose CsA produces significant increases in etoposide systemic exposure and leukopenia. These pharmacokinetic changes are consistent with inhibition by CsA of the multidrug transporter P-glycoprotein in normal tissues. Etoposide doses should be reduced by 50% when used with high-dose CsA in patients with normal renal and liver function. Alterations in the disposition of other multidrug resistance (MDR)-related drugs should be expected to occur with modulation of P-glycoprotein function in clinical trials.