The anaesthetic effects of ketamine and its major metabolite norketamine (NK) are explained by NMDA receptor antagonism. There is ample new evidence, firstly, that metabolites of NK, as the 2R,6R/2S,6S-enantiomers of hydroxynorketamin (HNK), exert neuro-modulating effects by AMPA-receptor activation and, secondly, that the plasma levels of NK after oral dosing are higher than after intravenous administration. Therefore, we evaluated pharmacokinetics and metabolism of a newly developed prolonged-release ketamine dosage form to confirm its suitability for chromic treatment of CNS-diseases (e.g. depression) according to the new "Ketamine Metabolite Paradigm". The dose-escalation study was performed in five consecutive periods (7 days wash-out) in 15 healthy subjects (5 females. 20-35 years, BMI 19.4-27.6 kg/m2). The racemic analytes were measured using validated LC-MS/MS methods. PR-K was safe and well tolerated.Tabled 15 mg i.v.10 mg p.o.20 mg p.o.40 mg p.o.80 mg p.o.AUC (ng×h/ml)52.3 ± 12.213.4 ± 13.333.5 ± 35.863.5 ± 42.6124 ± 72.9Cmax (ng/ml)29.9 ± 8.481.63 ± 1.333.70 ± 3.936.66 ± 4.2511.8 ± 6.56Tmax (h)-5.34 ± 1.185.70 ± 0.6495.87 ± 0.9156.27 ± 0.594*†F (%)-12.3 ± 10.715.3 ± 14.4*14.9 ± 8.94*14.6 ± 7.56*T½ (h)5.89 ± 2.614.96 ± 1.256.74 ± 2.02*7.21 ± 1.56#*7.68 ± 1.43#*†AUCNK/K1.79 ± 0.55721.6 ± 14.2#16.9 ± 8.58#*14.9 ± 8.50#*14.0 ± 6.50#*†AUCHNK/K0.334 ± 0.1287.33 ± 7.05#19.8 ± 16.4#*14.4 ± 8.99#*16.2 ± 7.93#*‡p<0.05 #vs. 5 mg i.v., *vs. 10 mg, †vs 20 mg, ‡vs. 40 mg p.o. (Wilcoxon) Open table in a new tab p<0.05 #vs. 5 mg i.v., *vs. 10 mg, †vs 20 mg, ‡vs. 40 mg p.o. (Wilcoxon) Prolonged-release ketamine undergoes dose-dependent "fist-pass" metabolism which generates substantially increased plasma exposure of downstream metabolites with potential neuro-modulating effects compared to ketamine after intravenous administration.

Hypercholesterolemia frequently occurs in patients treated with efavirenz who cannot be treated adequately with statins because of drug interactions. These patients may benefit from cholesterol-lowering therapy with ezetimibe. This study determined the influence of single-dose and multiple-dose efavirenz (400 mg/day for 9 days) on the pharmacokinetics and sterol-lowering of ezetimibe (10 mg) in 12 healthy subjects. In addition, the influence of efavirenz on genome-wide intestinal expression and in vitro function of ABCB1, ABCC2, UGT1A1, and OATP1B1 was studied. Efavirenz (multiple dose) had no influence on the pharmacokinetics and lipid-lowering functions of ezetimibe. Intestinal expression of enzymes and transporters (e.g., ABCB1, ABCC2, and UGT1A1) was not affected by chronic efavirenz. Efavirenz (single dose) slightly increased ezetimibe absorption and markedly decreased exposure to ezetimibe-glucuronide (single dose and multiple dose), which may be explained by inhibition of UGT1A1 and ABCB1 (in vitro data). Ezetimibe had no effect on the disposition of efavirenz. Consequently, ezetimibe may be a safe and efficient therapeutic option in patients with HIV infection.

Nuclear receptors such as the constitutive androstane receptor (CAR) are central factors that link drug exposure to the activities of drug metabolism and elimination. In order to determine the in vivo effects of efavirenz, a CAR activator, the expression of target genes was determined in duodenal biopsies obtained from 12 healthy volunteers before treatment and after 10 days of treatment with efavirenz; concomitant administration of the cholesterol inhibitor ezetimibe produced no significant difference. However, in in vitro studies, efavirenz significantly increased CYP2B6 expression in several cell types, suggesting that the drug transactivates CAR. This hypothesis is supported by our findings that there is significant induction of CAR target genes in in vivo peripheral blood mononuclear cells (PBMCs) isolated from healthy volunteers treated with multiple doses of efavirenz. The impact of efavirenz on hepatic metabolism in vivo was confirmed by significant changes in plasma 4 beta-hydroxycholesterol and bilirubin levels and the area under the curve (AUC) of efavirenz. Induction of CYP2B6 mRNA expression correlated with the decrease in the AUC of efavirenz (r = 0.61; P = 0.036). Taken together, our results provide evidence that efavirenz exerts compartment-specific inductive capacity in vivo.

Immunosuppressive therapy is frequently associated with hypercholesterolemia, calling for lipid-lowering treatment without adverse drug interactions. One option is treatment with the cholesterol absorption inhibitor ezetimibe. We have shown in vitro that ezetimibe and tacrolimus may interact in competition for intestinal UGT1A1 and ABCB1 at concentrations reached in gut lumen after oral administration. However, this clinical study in healthy volunteers showed that the expected pharmacokinetic interaction between ezetimibe and tacrolimus is not of clinical relevance.

Organ transplant recipients who have dyslipidemia related to immunosuppression may benefit from cholesterol-lowering therapy with ezetimibe, a substrate of ABCB1, ABCC2, and OATP1B1. Adverse pharmacokinetic interactions are hypothesized with sirolimus, which is a substrate of OATP1B1 and OATP1B3 and an inhibitor of ABCB1, OATP1B1, and OATP1B3 but not of ABCC2. However, competition between sirolimus and ezetimibe for ABCB1 and OATP1B1 is not of major clinical relevance, as confirmed in our randomized, controlled, single-dose study in healthy subjects.