MULTIPLE-DOSE LORAZEPAM KINETICS - SHUTTLING OF LORAZEPAM GLUCURONIDEBETWEEN THE CIRCULATION AND THE GUT DURING DAYTIME AND NIGHTTIME DOSING INTERVALS IN RESPONSE TO FEEDING

Lorazepam kinetics were examined in seven healthy males age 18 to 30 y ears after single- and multiple-dose lorazepam administration and in t he presence and absence of neomycin and cholestyramine to block the en terohepatic circulation of the drug. Methods used a simultaneous i.v./ p.o. dosing regimen with provision to measure lorazepam clearance duri ng day- and nighttime dosing intervals. The day-time steady-state clea rance of free lorazepam measured 7.55 +/- 1.95 ml/min/kg (mean +/- S.D .) and was identical to that observed after single-dose administration (7.68 +/- 3.19 ml/min/kg). Neomycin and cholestyramine increased lora zepam clearances 5 to 45% (P less-than-or-equal-to .05) as would be ex pected for interruption of an enterohepatic circulation and in keeping with previous observations under nonsteady-state conditions. Lorazepa m clearances were the same during the day as during the night, except in the presence of neomycin and cholestyramine, where night-time clear ances were significantly greater (10.16 +/- 3.52 vs. 8.77 +/- 2.43 ml/ min/kg, P less-than-or-equal-to .05). Urinary recoveries of lorazepam glucuronide, on the other hand, were greater during the day than durin g the night (114 +/- 11 vs. 77 +/- 15%, P less-than-or-equal-to .05) a nd in all cases were greater than 100% of the administered dose for th at interval. Thus, there is a diurnal variation in lorazepam eliminati on consistent with a fasting-induced increase in hepatic glucuronidati on during the night. This, combined with the relative inactivity of th e gut during this period, serves to trap the glucuronide and delay its transfer back to the systemic circulation and urine.