Jejunal permeability and hepatic extraction of fluvastatin in humans.
OBJECTIVE
The primary objective was to investigate the effective permeability and the hepatic extraction of fluvastatin, a new 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, during a jejunal perfusion in humans. The secondary objective was to investigate the relationship between human jejunal effective permeability values and physicochemical properties for four different drugs.


METHODS
Nine healthy male volunteers were included in the study, which consisted of two sequential study parts. In the first part, the jejunal effective permeability of fluvastatin, antipyrine, metoprolol, and atenolol was assessed with use of the regional jejunal perfusion approach (150 minutes, 2.0 ml/min). After a washout period of at least 5 days, the same subjects received an intravenous infusion of fluvastatin (20 minutes, 2.0 mg). Plasma samples were taken in both parts of the study and were analyzed for the content of fluvastatin.


RESULTS
The mean hepatic extraction of fluvastatin was 67% after the jejunal perfusion and 73% after the intravenous infusion. The half-life of fluvastatin was approximately 60 minutes after both administration routes. The jejunal effective permeability and the fraction absorbed both correlated (r2 = 0.968, p < 0.05; and r2 = 0.994, p < 0.05) with the partition coefficient (log D, pH 6.5) but not with the molecular size or the hydrogen bond number.


CONCLUSIONS
Fluvastatin is extracted by the liver to a large extent (about 70%) and has a short half-life after both oral and intravenous administration. In this study, the human jejunal effective permeability and the fraction absorbed for these four drugs were better predicted by log D (pH 6.5) than both the molecular size and the hydrogen bond number.
Lindahl
A
A
Department of Pharmacy, University of Uppsala, Sweden.
Sandström
R
R
Ungell
A L
AL
Abrahamsson
B
B
Knutson
T W
TW
Knutson
L
L
Lennernäs
H
H
D000328:Adult; D000983:Antipyrine / Q000737:chemistry / Q000493:pharmacokinetics; D001262:Atenolol / Q000737:chemistry / Q000493:pharmacokinetics; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D007408:Intestinal Absorption; D007583:Jejunum / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008790:Metoprolol / Q000737:chemistry / Q000493:pharmacokinetics; D010477:Perfusion
D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D000077340:Fluvastatin; D001262:Atenolol; D008790:Metoprolol; D000983:Antipyrine