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Pharmacokinetics of Midazolam Following Intravenous and Oral Administration in Patients with Chronic Liver Disease and in Healthy Subjects
Author(s) -
Pentikäinen P. J.,
Välisalmi L.,
Himberg J.J.,
Crevoisier C.
Publication year - 1989
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/j.1552-4604.1989.tb03327.x
Subject(s) - midazolam , pharmacokinetics , cirrhosis , medicine , bioavailability , elimination rate constant , hypnotic , oral administration , liver disease , gastroenterology , anesthesia , chronic liver disease , half life , pharmacology , volume of distribution , sedation
To study the effects of cirrhosis of the liver on the pharmacokinetics of midazolam single IV (7.5 mg as base) and p.o. (15.0 mg as base) doses of midazolam were administered to seven patients with cirrhosis of the liver and to seven healthy control subjects. One cirrhotic patient did not receive the oral dose. The distribution of midazolam in both study groups was alike as indicated by similar values of t 1/2 α, V 1 and V ss . Also the plasma protein binding of midazolam was unchanged in the patients with cirrhosis. The elimination of midazolam was significantly retarded in the patients as indicated by its lower total clearance (3.34 vs. 5.63 ml/min/kg), lower total elimination rate constant (0.400 vs. 0.721 h −1 ), and longer elimination half‐life (7.36 vs 3.80 h). The bioavailability of oral midazolam was significantly ( P < 0.05) higher in patients than controls (76% vs. 38%). The antipyrine‐half‐life was 32.4 h in the patients and 11.8 h in the controls. There were statistically significant ( P < 0.01) correlations between the clearances of the two drugs (r = 0.680) and between their half‐lives (r = 0.755). The hypnotic effects of midazolam were similar in both groups. However, on a pharmacokinetic basis a reduced dosage of midazolam to patients with advanced cirrhosis of the liver is recommended.