M, 65 j. Valproaat spiegels:
Medicatie: Paracetamol Doxycycline Meropenem Captopril Propofol Sufentanil Macrogol Zopiclon SDD Nadroparine Atenolol insuline
Wat is er aan de hand?
Interactie VALPROINEZUUR + CARBAPENEMS Dr. Stephanie Natsch Ziekenhuisapotheker-klinisch farmacoloog
Wat is het probleem? Bij toevoegen van een carbapenem bij patienten behandeld met valproïnezuur daalt de valproïnezuurspiegel sterk met als mogelijk gevolg therapiefalen bij epilepsie. Dit effect treedt vaak binnen 24 uur op. De combinatie moet worden vermeden. Monitoren van valproïnezuur is geen goede optie omdat het effect (spiegeldaling en convulsies) snel optreedt.
Wat zijn de gevolgen? Er zijn diverse case- reports van sterk verlaagde valproïnezuurspiegels die vaak optraden binnen 24 uur na toevoegen van meropenem, imipenem of ertapenem. Convulsies zijn gemeld. In één studie bij 10/23 patienten. De daling van de valproïnezuurspiegel is onafhankelijk van de dosis. De daling bedraagt ten minste 70%. De valproïnezuurspiegel bleef vaak ook na dosisverhoging van valproïnezuur tot meer dan 3000mg onder subtherapeutisch niveau. Herstel van de spiegels na stoppen van het carbapenem duurt +/- 8 dagen. Confounder: Convulsions are rarely reported with meropenem and one cannot fully exclude a contribution in the deterioration of epileptic activity.
Mean valproic acid (VPA) plasma concentrations before (n = 49), during (n = 41), and at 3 periods after meropenem (MER) treatment in all patients.
Mean valproic acid (VPA) plasma concentrations during (n = 6) and 1 to 7 days after (n = 4) meropenem (MER) treatment in patients receiving > 3000 mg VPA/d.
Hoe komt dit? The increase in clearance of VPA by meropenem does not involve enzyme induction because the enzyme. Induction process usually takes days to weeks to occur, but more probably enzyme inhibition. Slow recovery of VPA concentrations after administration of carbapenem antibiotics, which is longer than kinetically dictated by the carbapenem half-life is possibly due to the irreversible inhibition of beta-glucuronidase by meropenem. Recovery of VPA plasma levels is dependent on the rate of the enzyme turnover and not meropenem plasma half-life.
Farmacokinetiek van meropenem en valproïnezuur Meropenem: almost completely excreted unchanged in the urine within 12 hours after intravenous administration with a half-life of about one hour plasma protein binding of meropenem is 2% Valproate: extensively metabolized in the liver by glucuronidation (70%) and other minor pathways such as oxidation and hydroxylation. Glucuronidation is performed by the uridine disphosphate glucuronosyltransferase enzyme and a catalyzing cofactor uridine disphosphate glucuronic acid After excretion of glucuronidated valproate in the bile (45 55%), the metabolites undergo extensive enterohepatic recirculation. Valproate is extensively bound to plasma proteins (90 95%) reported half-lives vary from 5 to 20 hours
Mogelijke verklaringen: Rabbit model: meropenem accelerated the glucuronidation of VPA to VPAglucuronide (VPA-G) and inhibited the hydrolysis (de-conjugation) of VPA-G back to the parent compound, thus increasing the clearance of VPA and VPA-G. The study showed no replacement of protein-bound VPA from its binding sites or increase in unbound VPA plasma fraction. Another study clearly showed that panipenem, another carbapenem antibiotic, causes neither enzyme induction nor allosteric activation of UDP-glucuronosyltransferases (UGT), enzymes responsible for the glucuronidation of VPA. enhanced glucuronidation of valproate by up-regulation of the cofactor decreased hydrolysis of the glucuronized valproate Ø leads to increased hepatic intrinsic clearance and renal excretion of the drug.
Wat nu te doen? Één van de twee middelen vervangen Dat zal meestal valproïnezuur zijn à fenytoine Na staken meropenem herstel spiegel valproïnezuur na gem. 8 dagen. Dus let op in periode na staken meropenem!
Hebben we er ook nog wat aan? As meropenem increases the clearance of VPA and rapidly decreases its plasma concentration, it might be of value in the management of VPA overdose or toxicity, which is usually managed by extracorporeal therapies such as hemodialysis and hemoperfusion.