Alteration of drug-metabolizing enzyme activity in palliative care patients: Microdosed assessment of cytochrome P450 3A.

BACKGROUND: Cytochrome P450 3A is the most relevant drug-metabolizing enzyme in humans as it is involved in the elimination of 50% of marketed drugs. Nothing is known about the activity of cytochrome P450 3A in palliative care patients who have complicated symptoms often associated with a terminal illness. AIM: In order to improve drug dosing in end-of-life care and to avoid drug interactions, cytochrome P450 3A activity was determined in patients of a palliative care unit under real-life clinical conditions. DESIGN: As midazolam is an established marker substance for cytochrome P450 3A activity, this single-arm prospective trial was designed to obtain a 4-h pharmacokinetic profile of midazolam after oral administration of a 10-µg dose from each enrolled patient. Plasma concentrations of midazolam and its primary metabolite 1'-hydroxy-midazolam were quantified by mass spectrometry techniques. Cytochrome P450 3A activity was calculated as partial metabolic clearance from a limited sampling area under the curve. All other drugs taken by the participating patients were considered, as well as recent blood test results and patients' diagnoses. The trial was registered at German Clinical Trials Register ( www.drks.de ): DRKS00011753. SETTING/PARTICIPANTS: The trial was carried out at a university palliative care unit under real-life clinical conditions. Every patient admitted to the ward was screened for possible participation, independent of the individual performance status. RESULTS: Partial metabolic clearance of midazolam in palliative care patients was 31.7 ± 32.1 L/h. This was a highly significant 40% reduction (p < 0.0001) in comparison with the cytochrome P450 3A activity of healthy subjects. CONCLUSION: Dosing of cytochrome P450 3A substrate drugs (e.g. macrolide antibiotics, benzodiazepines, calcium channel blockers) needs to be adjusted in palliative care patients; otherwise, escalation of debilitating symptoms due to drug interactions might occur.

CYP3A5 and CYP3A4, but not ABCB1 polymorphisms affect tacrolimus dose-adjusted trough concentrations in kidney transplant recipients.

BACKGROUND: Tacrolimus (TAC), acting as a calcineurin inhibitor, is an immunosuppressant widely used after kidney transplantation. TAC requires blood concentration monitoring due to large interindividual variability in its pharmacokinetics and a narrow therapeutic index. Since genetic factors are considered responsible for a part of the observed pharmacokinetic variability, hereby SNPs within the CYP3A4, CYP3A5 and ABCB1 genes in kidney transplant patients of Polish Caucasian origin were investigated. PATIENTS & METHODS: A total of 241 patients treated with TAC through the first year after kidney transplantation were genotyped for the presence of common SNPs: rs776746:A>G (CYP3A5*3), rs35599367:C>T (CYP3A4*22), rs2740574:A>G (CYP3A4*1B) and rs1045642:C>T (ABCB1 3435C>T) using TaqMan(®) assays. RESULTS: CYP3A5 expressers received significantly higher weight-adjusted TAC doses, and were characterized by markedly lower C0 and dose adjusted C0 values in the course of treatment. CYP3A4*1B was significantly associated with TAC pharmacokinetics in univariate analysis. Impact of the CYP3A4*22 allele was significant only at particular time points, that is, 3 months after transplantation, with marginal significance 6 months after transplantation. The ABCB1 genotype did not influence TAC pharmacokinetics. Multivariate analysis of all the studied loci demonstrated that only the CYP3A5*1 (starting from month 1) and CYP3A4*22 alleles (at 3 and 6 months) were independent predictors of TAC dose-adjusted C0. CONCLUSION: Our results confirm the impact of the CYP3A4*22 allele on TAC pharmacokinetics, as a second significant genetic factor (in addition to the CYP3A5*1 allele) influencing TAC dose-adjusted blood concentrations in kidney transplant recipients.

Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects.

AIMS: The anticoagulant rivaroxaban is an oral, direct Factor Xa inhibitor for the management of thromboembolic disorders. Metabolism and excretion involve cytochrome P450 3A4 (CYP3A4) and 2J2 (CYP2J2), CYP-independent mechanisms, and P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) (ABCG2). METHODS: The pharmacokinetic effects of substrates or inhibitors of CYP3A4, P-gp and Bcrp (ABCG2) on rivaroxaban were studied in healthy volunteers. RESULTS: Rivaroxaban did not interact with midazolam (CYP3A4 probe substrate). Exposure to rivaroxaban when co-administered with midazolam was slightly decreased by 11% (95% confidence interval [CI] -28%, 7%) compared with rivaroxaban alone. The following drugs moderately affected rivaroxaban exposure, but not to a clinically relevant extent: erythromycin (moderate CYP3A4/P-gp inhibitor; 34% increase [95% CI 23%, 46%]), clarithromycin (strong CYP3A4/moderate P-gp inhibitor; 54% increase [95% CI 44%, 64%]) and fluconazole (moderate CYP3A4, possible Bcrp [ABCG2] inhibitor; 42% increase [95% CI 29%, 56%]). A significant increase in rivaroxaban exposure was demonstrated with the strong CYP3A4, P-gp/Bcrp (ABCG2) inhibitors (and potential CYP2J2 inhibitors) ketoconazole (158% increase [95% CI 136%, 182%] for a 400 mg once daily dose) and ritonavir (153% increase [95% CI 134%, 174%]). CONCLUSIONS: Results suggest that rivaroxaban may be co-administered with CYP3A4 and/or P-gp substrates/moderate inhibitors, but not with strong combined CYP3A4, P-gp and Bcrp (ABCG2) inhibitors (mainly comprising azole-antimycotics, apart from fluconazole, and HIV protease inhibitors), which are multi-pathway inhibitors of rivaroxaban clearance and elimination.

Bufalin inhibits CYP3A4 activity in vitro and in vivo.

AIM: To investigate the inhibitory interactions of bufalin and CYP3A4. METHODS: Recombinant human CYP3A4 was incubated with bufalin in vitro. Bufalin was administered ig and iv to Wistar rats to further estimate its impact on CYP3A4, and midazolam was given to index the activity of CYP3A4. RESULTS: The IC(50) of bufalin was 14.52 micromol/L. Bufalin affected CYP3A4 activity with increases in AUC(0-t) and t(1/2), and decreases in CL and the formation of 1-hydroxy-midazolam after ig or iv administration of midazolam (P<0.05). An increase in C(max) after ig bufalin administration (P<0.05) was observed. CONCLUSION: Bufalin showed a modest but significant inhibition of CYP3A4 both in vitro and in vivo. The likelihood of an interaction between bufalin and the CYP3A4-metabolized drugs in human might not be negated.