Contribution of the gastrointestinal tract to lorazepam conjugation and clonazepam nitroreduction.
Domestic pigs received single intravenous and oral doses of lorazepam or clonazepam (1 mg/kg), benzodiazepine derivatives biotransformed by glucuronide conjugation and nitroreduction, respectively. Blood samples were simultaneously drawn from portal venous and systemic venous sampling sites during 8 h after dosage. After intravenous dosage with either drug, the area under the serum concentration curve (AUC) for the intact drug, as well as for the principal metabolites (lorazepam glucuronide and 7-aminoclonazepam, respectively), was nearly identical between portal and systemic serum. After oral dosage, absolute systemic availability (relative to intravenous administration) of both lorazepam and clonazepam was incomplete (mean values: 29 and 49%, respectively); however, metabolite levels were also correspondingly lower between oral and intravenous dosages. First-pass hepatic extraction also occurred for both drugs, with mean systemic/portal AUC ratios of 0.60 for lorazepam and 0.74 for clonazepam. Pretreatment with neomycin (1.0 g) had a minimal effect on portal or systemic AUC for intact clonazepam after oral dosage, but 7-aminoclonazepam concentrations were reduced by neomycin pretreatment. Thus incomplete absorption, together with first-pass hepatic biotransformation, appears to explain the incomplete systemic availability of orally administered lorazepam or clonazepam. Biotransformation within the gastrointestinal tract or during absorption through the gastrointestinal mucosa contributes minimally.
Ochs
H R
HR
Abteilung für Allgemeine Innere Medizin (Zentrum für Innere Medizin) und Experimentelle Chirurgie, University of Bonn, FRG.
Greenblatt
D J
DJ
Eichelkraut
W
W
LeDuc
B W
BW
Powers
J F
JF
Hahn
N
N
D000284:Administration, Oral; D000818:Animals; D001711:Biotransformation; D002849:Chromatography, Gas; D002851:Chromatography, High Pressure Liquid; D002998:Clonazepam / Q000378:metabolism*; D004064:Digestive System / Q000378:metabolism*; D007275:Injections, Intravenous; D007700:Kinetics; D008140:Lorazepam / Q000378:metabolism*; D009574:Nitro Compounds / Q000378:metabolism*; D010084:Oxidation-Reduction; D013552:Swine
D009574:Nitro Compounds; D002998:Clonazepam; D008140:Lorazepam