C08CA01 - Amlodipine |
Propably not porphyrinogenic |
PNP |
Rationale
Mechanism-based CYP 3A4-inhibitor, probably of too low potency to be porphyrogenic. No significant inhibition or induction of CYP 3A4 is observed in clinical use. One publication reports an acute attack following the use of amlodipine, but there are 37 reports (per January 2010) of safe use in carriers of acute porphyria. Dyspeptic symptoms may cause potentially porphyrogenic reductions in food intake. Effect on PXR-activation by plasma calcium-deficit hypo-insulinemia can not be excluded, but are reported to be rare, and seemingly without clinical significance with regard to porphyrogenic ALAS1-induction.
Chemical description
3-Ethyl 5-methyl 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methylpyridine-3,5-dicarboxylate. M =408.9. 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
Amlodipine is a dihydropyridine calcium-channel blocker. It is used in the management of hypertension and angina pectoris. Amlodipine exerts its effect by relaxing arterial and arteriolar smooth muscle. The common side effects are nausea, acute abdominal pain, dyspepsia and dyspnoea. Less common side effects are insomnia, irritability, depressive mode, back-pain, myalgia, arthalgia, paraesthesia and peripheral neuropathy.
Hepatic exposure
Possibly significant.
Metabolism and pharmacokinetics
Amlodipine is extensively metabolized in the liver by CYP 3A4. It is a substrate and only moderately potent (Ki=4.9 uM) inhibitor of CYP 3A4. It is not a substrate of P-Gp. Listed as irreversible CYP 3A4-inhibitor (kinact=0.35; Ki=2.6 uM; plasma concentration=0.1-0.4 uM. Partition ratio data not available)(Zhou, 2007). On CYP-oxidation the tertiary amine function undergoes N-dealkylation forming a reactive intermediate which attacks the heme-component of the enzyme (Hollenberg, 2008). The therapeutic plasma concentration of the drug in comparison to the relatively high concentration needed for half-maximal CYP 3A4- inhibition (Ki=2,6 uM)) makes it less likely for amlodipine to cause irrversible CYP-inhibition and heme-destruction of a degree to cause a significant ALAS1-induction. On the other hand it is used in long-term therapy, with a possible chronic low-intensive drain of hepatic heme. In clinical use, there are no observations of significant inibition or induction of CYP-metabolism of other drugs (Nishio, 2005; Meredith, 1992).
Preclinical data
Although dihydropyridines such as nifedipine are highly porphyrinogenic in chick embryo liver cell cultures, amlodipine because of its basic amino side chain (pKa= 8.6) is water-soluble and less likely to be an inducer of ALA-synthase(Gorchein, 1997).
Personal communication
C.Andersson 2004; 10 patient reports in carriers of AIP. S.Thunell 2004; 4 patient reports in carriers of AIP.
Published experience
Report of attack: Kepple, 1997. Reports of uneventful use: 1.Gorchein 1997. 2. Cinemre, 2007.
IPNet drug reports
Uneventful use reported in 63 patients with acute porphyria.
References
- Scientific articles
- Cinemre et al, 2007. Safety of amlodipine use in patients with acute intermittent porphyria. Br J Clin Pharmacol 1997. #1273
- Hollenberg PF et al, 2008. Mechanism-Based Inactivation of Human Cytochromes P450s: Experimental Characterization, Reactive Intermediates, and Clinical Implications. #1275
- Kepple A et al, 1997. Amlodipine-induced acute intermittent porphyria exacerbation. #1276
- Ma B et al, 2000. Drug interactions with calcium channel blockers: possible involvement of metabolite-intermediate complexation with CYP3A. #1277
- Meredith PA, 1992. Clinical pharmacokinetics of amlodipine. Clin Pharmacokinet. 1992 Jan;22(1):22-31. PMID 1532771. #1279
- Nishio S et al, 2005. Interaction between Amlodipine and Simvastatin in Patients with Hypercholesterolemia and Hypertension. #1280
- 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
- Gorchein A. Drug treatment of hypertension in acute intermittentporphyria: doxazosin and amlodipine. Br J Clin Pharmacol 1997; 43: 339â-40. PMID 9088595. #1274
- Drug reference publications
- Martindale 2009. #1278
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