The effect of a long term epidural infusion of ropivacaine on CYP2D6 activity.
BACKGROUND
Ropivacaine and one of its metabolites, pipecoloxylidide, inhibit CYP2D6 in. human liver microsomes in vitro with K(i) values of 5 microM (1.4 mg/L) and 13 microM (3.6 mg/L), respectively. We investigated the effect of a 50 h continuous epidural infusion of ropivacaine 2 mg/mL at a rate of 14 mL/h on CYP2D6 activity.


METHODS
Nineteen patients (41-85 yr) undergoing hip or knee replacement, all extensive metabolizers with respect to CYP2D6 activity, were included. Medications known to inhibit or be metabolized by CYP2D6, or known to be strong inhibitors/inducers of CYP1A2 or CYP3A4 were not allowed. Patients received 10 mg debrisoquine (a marker for CYP2D6 activity) before surgery and after 40 h epidural infusion. The metabolic ratio (MR) for debrisoquine hydroxylation was calculated as the amount of debrisoquine/amount of 4-OH-debrisoquine excreted in 0-10 h urine.


RESULTS
The median (range) of MR before and after ropivacaine were 0.54 (0.1-3.4) and 1.79 (0.3-6.7), respectively. The Hodges Lehman estimate of the ratio MR after/MR before ropivacaine was 2.2 with a 95% confidence interval 1.9-2.7 (P < 0.001).


CONCLUSIONS
A continuous epidural infusion of ropivacaine inhibits CYP2D6 activity in patients who are extensive metabolizers resulting in a twofold increase in the MR for debrisoquine hydroxylation. However, since none of the patients was converted into a functional poor metabolizer (MR >12.6), the effect on the metabolism of other drugs metabolized by CYP2D6 is unlikely to be of major clinical importance.
Wink
Jeroen
J
Department of Anesthesiology, Leiden University Medical Centre, Leiden, The Netherlands. j.wink@lumc.nl
Veering
Bernadette Th
BT
Kruit
Michel
M
Burm
Anton G L
AG
Huledal
Gunilla A I
GA
Ekström
Gunilla Y
GY
Stienstra
Rudolf
R
van Kleef
Jack W
JW
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000577:Amides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D015360:Analgesia, Epidural; D000779:Anesthetics, Local / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D019644:Arthroplasty, Replacement, Hip; D019645:Arthroplasty, Replacement, Knee; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003647:Debrisoquin / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000652:urine; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D006900:Hydroxylation; D007263:Infusions, Parenteral; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008875:Middle Aged; D009426:Netherlands; D000077212:Ropivacaine; D013379:Substrate Specificity; D013548:Sweden; D013997:Time Factors; D016896:Treatment Outcome
D000577:Amides; D000779:Anesthetics, Local; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; C012359:4-hydroxydebrisoquin; D000077212:Ropivacaine; D019389:Cytochrome P-450 CYP2D6; D003647:Debrisoquin