C08CA05 - Nifedipine |
Propably not porphyrinogenic |
PNP |
Rationale
Nifedipine is a substrate of CYP 3A4 and CYP 2D6. It is a reversible inhibitor of CYP 3A4, CYP 2D6 and CYP 2C9. Conflicting in vitro observations regarding capacity for CYP-inhibition/induction. Observed to have been tolerated by 8 carriers of acute porphyria ( per February 2010). Effect on PXR-activation of plasma calcium-deficit induced hypo-insulinemia cannot be excluded, but seems to be very rare and is e.g. under amlodipine treatment seemingly without clinical significance with regard to porphyrogenic ALAS1 induction.
Chemical description
Dimethyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)pyridine-3,5-dicarboxylate. M= 346. Dihydropyridine derivative. Contains one cyclic tertiary amine group, shown in other drugs to cause irreversible or quasi-irreversible (nicardipine) inhibition (Ma, 2000; Hollenberg, 2008). Other cyclic tertiary amine MB-inhibitors have been shown to give rise to 2,3 dihydropyridinium metabolites, which bind to the CYP-apoprotein without loss of spectrally detectable heme (Hollenberg, 2008).
Therapeutic characteristics
Nifedipine is a dihydropyridine calcium-channel blocker. It is a peripheral and coronary vasodilator, but, unlike the rate-limiting calcium-channel blockers verapamil or diltiazem, has little or no effect on cardiac conduction and negative inotropic activity is rarely seen at therapeutic doses. Use of nifedipine results primarily in vasodilatation, with reduced peripheral resistance, blood pressure, and afterload, increased coronary blood flow, and a reflex increase in heart rate. This in turn results in an increase in myocardial oxygen supply and cardiac output. The most common adverse effects of nifedipine are nausea, constipation, dizziness, flushing, headache, hypotension, peripheral oedema, tachycardia, and palpitations.
Hepatic exposure
Probably significant.
Metabolism and pharmakokinetics
Nifedipine was first reported to be metabolised by CYP 3A4, and it was commonly agreed that the oxidation of 1,4-dihydro-pyridine into pyridine is catalysed by CYP3A4 (Katoh, 2000; Zhou, 2005). Nifedipine is not a substrate of P-gp (Zhou, 2007). It is a substrate of CYP 3A4 and CYP 2D6. It is also an inhibitor of several CYP-enzymes such as CYP 1A1, CYP 1A2, CYP 2C9, CYP 2D6 and CYP 3A4 (Ma, 2000; Katoh, 2000; Rendic 2002). It is a reversible inhibitor of CYP 3A4 (Ki= 10–22 uM; IC50= 30 uM)(Zhou, 2007; Ma, 2000). It undergoes extensive hepatic first-pass metabolism. Bioavailability of oral liquid-filled capsules is between 45 and 56%, but is lower for longer-acting formulations.
Preclinical data
Nifedipine did not cause suicidal destruction of cytochrome P-450 with concomitant heme destruction in chick embryo liver microsomes (Marks,1986).
Personal communication
C.Andersson 2004; 3 patient reports of safe use.
Published experience
Reports of uneventful use: 1. Bahdoria, 1988. 2. Kauppinen, 1992. Warned against : James, 2000.
IPNet drug reports
Uneventful use reported in 4 patients with acute porphyria.
References
- Scientific articles
- Bahdoria et al, 1988. Safe use of clonidine, nifedipine and vitamin K in hepatic porphyria. #1290
- Hollenberg PF et al, 2008. Mechanism-Based Inactivation of Human Cytochromes P450s: Experimental Characterization, Reactive Intermediates, and Clinical Implications. #1275
- Jamesand Hift. Porphyrias. Br J Anaesth 2000; 85, 143-53: use with extreme caution only. PMID 10928003. #4406
- Katoh M et al, 2000. Prediction of DDI, Dihydroksypyridine ca-antagonists. #1284
- Kauppinen and Mustajoki. Prognosis of acute porphyria: Occurrence of acute attacks, precipitating factors,and assocciated diseases. Medicine 1992; 71, 1-13. #1218
- Marks, GS, Can J Physiol Pharmacol 1986, The effects of dihydropyridine calcium antagonists on heme biosynthesis in chick embryo liver cell culture. PMID 3730927. #4407
- Rendic S et al, Drug Metabolism Reviews 2002, Summary of information on human cyp enzymes Human P40 metabolism data. #1285
- Zhou SF et al, 2005. Mechanism-Based Inhibition of Cytochrome P450 3A4 by Therapeutic Drugs. #1281
- Zhou SF et al, 2007. Clinically Important Drug Interactions Potentially Involving Mechanism-based Inhibition of Cytochrome P450 3A4 and the Role of Therapeutic Drug Monitoring. #1282
- Drug reference publications
- Martindale 2009, online. #1293
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