Rifampin enhances cytochrome P450 (CYP) 2B6-mediated efavirenz 8-hydroxylation in healthy volunteers

The effect of rifampin on the in vivo metabolism of the antiretroviral drug efavirenz was evaluated in healthy volunteers. In a cross-over placebo control trial, healthy subjects (n = 20) were administered a single 600 mg oral dose of efavirenz after pretreatment with placebo or rifampin (600 mg/day for 10 days). Plasma and urine concentrations of efavirenz, 8-hydroxyefavirenz and 8,14-dihydroxyefavirenz were measured by LC-MS/MS. Compared to placebo treatment, rifampin increased the oral clearance (by ∼2.5-fold) and decreased maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC0-∞) of efavirenz (by ∼1.6- and ∼2.5-fold respectively) (p < 0.001). Rifampin treatment substantially increased the Cmax and AUC0-12h of 8-hydroxyefavirenz and 8,14-dihydroxyefavirenz, metabolic ratio (AUC0-72h of metabolites to AUC0-72h efavirenz) and the amount of metabolites excreted in urine (Ae0-12hr) (all, p < 0.01). Female subjects had longer elimination half-life (1.6-2.2-fold) and larger weight-adjusted distribution volume (1.6-1.9-fold) of efavirenz than male subjects (p < 0.05) in placebo and rifampin treated groups respectively. In conclusion, rifampin enhances CYP2B6-mediated efavirenz 8-hydroxylation in vivo. The metabolism of a single oral dose of efavirenz may be a suitable in vivo marker of CYP2B6 activity to evaluate induction drug interactions involving this enzyme

Predictive value of known and novel alleles ofCYP2B6 for efavirenz plasma concentrations in HIV-infected individuals

© 2008 American Society for Clinical Pharmacology and TherapeuticsTo assess the association of CYP2B6 allelic diversity with efavirenz (EFV) pharmacokinetics, we performed extensive genotyping of 15 relevant single nucleotide polymorphism in 169 study participants, and full resequencing of CYP2B6 in individuals with abnormal EFV plasma levels. Seventy-seven (45.5%) individuals carried a known (CYP2B66,11,15, or 18) or new loss/diminished-function alleles. Resequencing defined two new loss-of-function alleles: allele 27 (marked by 593T&gt;C [M198T]), that results in 85% decrease in enzyme activity and allele 28 (marked by 1132C&gt;T), that results in protein truncation at arginine 378. Median AUC levels were 188.5 g h/ml for individuals homozygous for a loss/diminished-function allele, 58.6 g h/ml for carriers, and 43.7 g h/ml for noncarriers (P&lt;0.0001). Individuals with a poor metabolizer genotype had a likelihood ratio of 35 (95% CI, 11–110) of presenting very high EFV plasma levels. CYP2B6 poor metabolizer genotypes explain to a large extent EFV pharmacokinetics and identify individuals at risk of extremely elevated EFV plasma levels

Sphagnum growth under N saturation: interactive effects of water level and P or K fertilization

Abstract Sphagnum biomass is a promising material that could be used as a substitute for peat in growing media and can be sustainably produced by converting existing drainage‐based peatland agriculture into wet, climate‐friendly agriculture (paludiculture). Our study focuses on yield maximization of Sphagnum as a crop. We tested the effects of three water level regimes and of phosphorus or potassium fertilization on the growth of four Sphagnum species (S. papillosum, S. palustre, S. fimbriatum, S. fallax). To simulate field conditions in Central and Western Europe we carried out a glasshouse experiment under nitrogen‐saturated conditions. A constant high water table (remaining at 2 cm below capitulum during growth) led to highest productivity for all tested species. Water table fluctuations between 2 and 9 cm below capitulum during growth and a water level 2 cm below capitulum at the start but falling relatively during plant growth led to significantly lower productivity. Fertilization had no effect on Sphagnum growth under conditions with high atmospheric deposition such as in NW Germany (38 kg N, 0.3 kg P, 7.6 kg K·ha−1·year−1). Large‐scale maximization of Sphagnum yields requires precise water management, with water tables just below the capitula and rising with Sphagnum growth. The nutrient load in large areas of Central and Western Europe from atmospheric deposition and irrigation water is high but, with an optimal water supply, does not hamper Sphagnum growth, at least not of regional provenances of Sphagnum

Selective induction of human hepatic cytochromes P450 2B6 and 3A4 by metamizole

The pyrazolone drug metamizole is a widely used analgesic. Analysis of liver microsomes from patients treated with metamizole revealed selectively higher expression of cytochromes P450, CYP2B6 and CYP3A4 (3.8- and 2.8-fold, respectively), and 2.9-fold higher bupropion hydroxylase activity compared with untreated subjects. Further investigation of metamizole and various derivatives on different potential target genes in human primary hepatocytes demonstrated time- and concentration-dependent induction by metamizole of CYP2B6 (7.8- and 3.1-fold for mRNA and protein, respectively, at 100 M) and CYP3A4 (2.4- and 2.9-fold, respectively), whereas other genes (CYP2C9, CYP2C19, CYP2D6, NADPH:cytochrome P450 reductase, ABCB1, constitutive androstane receptor (CAR), pregnane X receptor (PXR)) were not substantially altered. Using reporter gene assays, we show that metamizole is not acting as a direct ligand to either PXR or CAR, suggesting a phenobarbital-like mechanism of induction. These data warrant further studies to elucidate the drug-interaction potential of metamizole, especially in patients with long-term treatment.T Saussele, O Burk, J K Blievernicht, K Klein, A Nussler, N Nussler, J G Hengstler, M Eichelbaum, M Schwab, and U M Zange