Metabolism of ropivacaine in humans is mediated by CYP1A2 and to a minor extent by CYP3A4: an interaction study with fluvoxamine and ketoconazole as in vivo inhibitors.
BACKGROUND
Potential drug-drug interactions can be identified in vitro by exploring the importance of specific cytochrome P450 (CYP) isozymes for drug metabolism. The metabolism of the local anesthetic ropivacaine to 3-hydroxyropivacaine and (S)-2',6'-pipecoloxylidide was shown in vitro to be dependent on CYP1A2 and 3A4, respectively. In this in vivo model study we quantitated the role of these 2 isozymes for the metabolism of ropivacaine.


METHODS
In a randomized, 3-way crossover study, 12 healthy subjects received a single dose of 40 mg ropivacaine intravenously alone or combined either with 25 mg fluvoxamine as a CYP1A2 inhibitor or with 100 mg ketoconazole as a CYP3A4 inhibitor twice daily for 2 days. Venous plasma and urine samples were collected over 10 hours and 24 hours, respectively. The samples were analyzed for ropivacaine base, 3-hydroxyropivacaine, and (S)-2',6'-pipecoloxylidide.


RESULTS
Coadministration with fluvoxamine decreased the mean total plasma clearance of ropivacaine from 354 to 112 mL/min (68%), whereas ketoconazole decreased plasma clearance to 302 mL/min (15%). The relative changes in unbound plasma clearance were similar to the changes in total plasma clearance. The ropivacaine half-life (t1/2) of 1.9 hours was almost doubled during fluvoxamine administration and the plasma concentration at the end of infusion increased slightly, whereas the corresponding parameters after ketoconazole administration remained unchanged. Coadministration with ketoconazole almost abolished the (S)-2',6'-pipecoloxylidide concentrations in plasma, whereas fluvoxamine administration increased the (S)-2',6'-pipecoloxylidide levels. The fraction of dose excreted as 3-hydroxyropivacaine in urine decreased during fluvoxamine administration from 39% to 13%.


CONCLUSIONS
CYP1A2 is the most important isozyme for the metabolism of ropivacaine. Drug-drug interactions with strong inhibitors of this isozyme could be of clinical relevance during repeated administration. A potent inhibitor of CYP3A4 causes a minor decrease in clearance, which should be of no clinical relevance.
Arlander
E
E
Department of Clinical Research and Development, Astra Pain Control AB, Södertälje, Sweden.
Ekström
G
G
Alm
C
C
Carrillo
J A
JA
Bielenstein
M
M
Böttiger
Y
Y
Bertilsson
L
L
Gustafsson
L L
LL
D000328:Adult; D000577:Amides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000779:Anesthetics, Local / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D016666:Fluvoxamine / Q000494:pharmacology; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D012016:Reference Values; D000077212:Ropivacaine; D013997:Time Factors
D000577:Amides; D000779:Anesthetics, Local; D004791:Enzyme Inhibitors; D000077212:Ropivacaine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016666:Fluvoxamine; D007654:Ketoconazole