Dietary salt increases first-pass elimination of oral quinidine.
BACKGROUND
Some cytochrome P450 (CYP) enzymes, including CYP3A, are expressed not only in the liver but also in the intestine; the latter may therefore be an important site of drug disposition. Animal data suggests that dietary salt modulates expression of renal CYPs. We therefore hypothesized that intestinal CYP3A may be similarly modulated by dietary salt.


METHODS
The effect of changes in dietary salt on the disposition of two CYP3A substrates, quinidine (administered orally and intravenously) and 14C-erythromycin (administered intravenously) were determined after normal volunteers were given high-salt (400 mEq/day) and low-salt (10 mEq/day) diets for 7 to 10 days each.


RESULTS
Plasma concentrations after oral quinidine were significantly lower during the high-salt phase, with the difference between the two treatments attributable to changes within the first 1 to 4 hours after administration. For example, the area under the plasma concentration-time curve for the first hour after drug administration was 0.56 +/- 0.38 microgram.hr/ml for the high-salt diet compared with 1.57 +/- 0.60 micrograms.hr/ml for the low-salt diet (p < 0.05). Similarly, the peak plasma concentration (Cmax) achieved was lower and the time to reach Cmax was later for the high-salt diet (p < 0.05). In contrast, the terminal phase elimination half-lives were similar for the two diets, and no differences in disposition were found with the intravenous drug. The erythromycin breath test was unaffected by the dietary treatments.


CONCLUSIONS
These results indicate an effect of dietary salt on the presystemic disposition of orally administered quinidine. Although the mechanism(s) of CYP3A activity modulation is unknown, this finding may be important in determining drug availability in conditions associated with abnormal salt homeostasis.
Darbar
D
D
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-6602, USA.
Dell'Orto
S
S
Mörike
K
K
Wilkinson
G R
GR
Roden
D M
DM
D000284:Administration, Oral; D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D007422:Intestines / Q000201:enzymology*; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000187:drug effects* / Q000378:metabolism; D011802:Quinidine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D012016:Reference Values; D012982:Sodium, Dietary / Q000008:administration & dosage*; D013997:Time Factors
D000889:Anti-Arrhythmia Agents; D012982:Sodium, Dietary; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D011802:Quinidine