No alteration of Cyp3A4 activity after major hepatectomy in the early postoperative period - A prospective before-after study.

BACKGROUND: The impact of major liver resection (LR) on the detoxifying function of the remaining liver tissue as represented by CYP3A activity has yet to be assessed. Therefore, this study evaluates the changes in CYP3A activity between preoperative values and after liver resection. MATERIAL AND METHODS: To determine CYP3A activity, midazolam (MDZ) was used as a marker substance, 3 µg were applied intravenously one day before surgery and on the 3rd day after surgery. Subsequently blood was withdrawn at 0, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3, 4 and 6 h post application of the study drug. Plasma MDZ and 1-OH-MDZ concentration was assessed using a LC-MS/MS method. Volumetric analysis of the resected liver was done by syngo.CT liver analysis software (Siemens Healthineers) using preoperative multidetector computed tomography. RESULTS: N = 13 (8 male/5 female) patients were included in this study and received preoperative evaluation, 11 patients were studied also after liver resection. The mean age was 62 (±15.3) years with a mean BMI of 23.6 ± 4.8 kg/m2. No patient suffered from acute liver dysfunction postoperatively. None of the pharmacokinetic parameters assessed were significantly altered by liver resection. CYP3A activity over time was not significantly reduced by major liver resection. CONCLUSION: This study gives first time data on the impact of major liver resection on CYP3A activity. It was shown that MDZ clearance representing in vivo CYP3A activity is not altered by major liver resection. This suggests no dose adjustment of commonly applied drugs which are CYP3A substrates needs to be carried out.

Higher chlorzoxazone clearance in obese children compared with nonobese peers.

AIMS: To test the in vivo activity of Cytochrome P450 (CYP) 2E1 in obese children vs. nonobese children, aged 11-18 years. Secondly, whether the activity of CYP2E1 in these patients is associated with NALFD, diabetes or hyperlipidaemia. METHODS: Seventy children were divided into groups by body mass index (BMI) standard deviation score (SDS). All children received 250 mg oral chlorzoxazone (CLZ) as probe for CYP2E1 activity. Thirteen blood samples and 20-h urine samples were collected per participant. RESULTS: Obese children had an increased oral clearance and distribution of CLZ, indicating increased CYP2E1 activity, similar to obese adults. The mean AUC0-∞ value of CLZ was decreased by 46% in obese children compared to nonobese children. The F was was increased twofold in obese children compared to nonobese children, P < 0.0001. Diabetic biomarkers were significantly increased in obese children, while fasting blood glucose and Hba1c levels were nonsignificant between groups. Liver fat content was not associated with CLZ Cl. CONCLUSION: Oral clearance of CLZ was increased two-fold in obese children vs. nonobese children aged 11-18 years. This indicates an increased CYP2E1 activity of clinical importance, and dose adjustment should be considered for CLZ.

The NTCP-inhibitor Myrcludex B: Effects on Bile Acid Disposition and Tenofovir Pharmacokinetics.

Myrcludex B acts as a hepatitis B and D virus entry inhibitor blocking the sodium taurocholate cotransporting polypeptide (SLC10A1). We investigated the effects of myrcludex B on plasma bile acid disposition, tenofovir pharmacokinetics, and perpetrator characteristics on cytochrome P450 (CYP) 3A. Twelve healthy volunteers received 300 mg tenofovir disoproxil fumarate orally and 10 mg subcutaneous myrcludex B. Myrcludex B increased total plasma bile acid exposure 19.2-fold without signs of cholestasis. The rise in conjugated bile acids was up to 124-fold (taurocholic acid). Coadministration of tenofovir with myrcludex B revealed no relevant changes in tenofovir pharmacokinetics. CYP3A activity slightly but significantly decreased by 29% during combination therapy. Myrcludex B caused an asymptomatic but distinct rise in plasma bile acid concentrations and had no relevant impact on tenofovir pharmacokinetics. Changes in CYP3A activity might be due to alterations in bile acid signaling. Long-term effects of elevated bile acids will require critical evaluation.

[Management of chronic pain using extended release tilidine : Quality of life and implication of comedication on tilidine metabolism]. / Management von chronischem Schmerz mit retardiertem Tilidin : Lebensqualität und Bedeutung der Komedikation für den Tilidinmetabolismus.

BACKGROUND AND OBJECTIVES: The synthetic opioid tilidine is often used in chronic pain treatment. However, the activation via metabolism in patients with concomitant medication and reduced liver or kidney function is not thoroughly investigated. We therefore studied pain treatment efficacy, health-related quality of live and the metabolism of tilidine in patients with chronic pain. METHODS AND MATERIALS: In all, 48 patients, who were on a stable dose of oral prolonged release tilidine for at least 7 days, were included in this observational multicenter study. Liver and kidney function were assessed in routine blood samples, concentrations of tilidine, nortilidine and bisnortilidine were determined using a validated LC/MS/MS method. Comedication was registered and patients experience with regard to quality of life, pain, gastrointestinal symptoms and adverse events was assessed in standardised questionnaires. RESULTS: On average a daily dose of 180 mg tilidine was taken. Dose normalized plasma concentrations of the active metabolite nortilidine ranged between 1.6 ng/ml and 76.5 ng/ml (mean 29.2 ± 25.1 ng/ml). Ratios between tilidine and nortilidine were on average 0.28 (median = 0.13, standard deviation = 0.67). Patients were on 1 to 14 different concomitant medications. About 66% of the patients had sufficient pain treatment. Almost no opioid-induced constipation was observed. Only few patients had decreased kidney or liver function which did not result in elevated nortilidine concentrations. CONCLUSION: Pain treatment using tilidine resulted in variable nortilidine concentrations which are obviously not strongly influenced by comedication or reduced liver or kidney function. Only a few side effects were observed with almost no opioid-induced constipation.

European Pain Federation position paper on appropriate opioid use in chronic pain management.

Poorly controlled pain is a global public health issue. The personal, familial and societal costs are immeasurable. Only a minority of European patients have access to a comprehensive specialist pain clinic. More commonly the responsibility for chronic pain management and initiating opioid therapy rests with the primary care physician and other non-specialist opioid prescribers. There is much confusing and conflicting information available to non-specialist prescribers regarding opioid therapy and a great deal of unjustified fear is generated. Opioid therapy should only be initiated by competent clinicians as part of a multi-faceted treatment programme in circumstances where more simple measures have failed. Throughout, all patients must be kept under close clinical surveillance. As with any other medical therapy, if the treatment fails to yield the desired results and/or the patient is additionally burdened by an unacceptable level of adverse effects, the overall management strategy must be reviewed and revised. No responsible clinician will wish to pursue a failed treatment strategy or persist with an ineffective and burdensome treatment. In a considered attempt to empower and inform non-specialist opioid prescribers, EFIC convened a European group of experts, drawn from a diverse range of basic science and relevant clinical disciplines, to prepare a position paper on appropriate opioid use in chronic pain. The expert panel reviewed the available literature and harnessed the experience of many years of clinical practice to produce these series of recommendations. Its success will be judged on the extent to which it contributes to an improved pain management experience for chronic pain patients across Europe. SIGNIFICANCE: This position paper provides expert recommendations for primary care physicians and other non- specialist healthcare professionals in Europe, particularly those who do not have ready access to specialists in pain medicine, on the safe and appropriate use of opioid medications as part of a multi-faceted approach to pain management, in properly selected and supervised patients.

Morphine-6-glucuronide is responsible for the analgesic effect after morphine administration: a quantitative review of morphine, morphine-6-glucuronide, and morphine-3-glucuronide.

BACKGROUND: Morphine-6-glucuronide (M6G) is a strong µ-receptor agonist with higher affinity than morphine itself. It has been suggested that M6G contributes to the analgesic effect after administration of morphine, but the extent of its contribution remains unclear. METHODS: In order to elucidate the relative contribution of both drugs to the overall analgesic effect mediated by the µ-receptor, published data on µ-receptor binding, plasma protein binding, concentrations [preferably area under the concentration-time curve (AUC)] of morphine and M6G in blood or cerebrospinal fluid (CSF), or concentration ratios were used to calculate free CSF concentration corrected for receptor binding for each compound. To compare different routes of administration, free CSF concentrations of M and M6G corrected for potency were added and compared with oral administration. RESULTS: Based on AUC data, there is a major contribution of M6G to the overall analgesic effect; the mean contributions being estimated as 96.6%, 85.6%, 85.4%, and 91.3% after oral, s.c., i.v., and rectal administration of morphine, respectively. In patients with renal insufficiency, 97.6% of the analgesic effect is caused by M6G when morphine is given orally. Owing to accumulation of M6G over time in these patients, morphine may be regarded as a prodrug. CONCLUSIONS: When administering morphine to patients, the analgesic effect is mainly caused by M6G instead of morphine itself, irrespective of the route of administration. Therefore, the patient's kidney function plays a key role in determining the optimal daily dose of morphine.

A nanogram dose of the CYP3A probe substrate midazolam to evaluate drug interactions.

The objective of the study was to establish an in vivo method for assessing cytochrome P450 3A (CYP3A) activity using therapeutically inert nanogram doses of midazolam. We administered four escalating single doses of oral midazolam (0.0001-3 mg) to 12 healthy participants, stratified according to CYP3A5 carrier status, to assess pharmacokinetics linearity. We then evaluated the interactions with the CYP3A inhibitor ketoconazole (400 mg q.d.) after nanogram and regular doses of midazolam. Area under the plasma concentration-time curve (AUC) and peak plasma concentration (C(max)) were linear over the entire range of doses. Ketoconazole reduced midazolam oral clearance by 92.8%. AUC and C(max) increased by 1,540 and 363%, respectively. CYP3A5 carrier status had no influence on midazolam oral clearance or its inhibition by ketoconazole. This is the first study showing that midazolam pharmacokinetics is linear in a 30,000-fold concentration range, and therefore that nano- and microgram doses of midazolam can reliably predict the pharmacokinetics of midazolam in therapeutic doses and can be used to assess CYP3A activity even in the presence of strong CYP3A inhibitors.

[Candida infections in the elderly]. / Candida-Infektionen im hohen Alter.

Candida infections of the skin, mucous membranes as well as of internal organs may be more frequent and more serious in the elderly. There are several biological reasons for this, for example, alterations in the immune system. Whereas Candida albicans remains the major pathogen, there has been a relative increase of Candida glabrata infections. This species is associated with higher mortality. Furthermore, C. glabrata is in general less susceptible to fluconazole, so that this drug does not represent the agent of first choice for the treatment of yeast infections. The choice of the antimycotic agent must take into consideration their inherent side effects and interaction profiles; echinocandins play a particular role in the treatment of yeast infections in the elderly. These drugs have low toxicities, low potential for interactions with co-medications, as well as broad and good activities against yeasts.

Determining the time course of CYP3A inhibition by potent reversible and irreversible CYP3A inhibitors using A limited sampling strategy.

We established a new limited sampling strategy to assess CYP3A activity and evaluated the time course of reversible (voriconazole) and irreversible (ritonavir) CYP3A inhibition. In this randomized trial, two groups, each with eight healthy participants, received CYP3A inhibitors voriconazole or ritonavir orally for 9 days, with 3 mg midazolam (MDZ) administered before the inhibitor treatment, on days 1, 2, 3, 5, 8, and 9 during inhibitor treatment, and on days 10, 11, and 12 (3 days) after discontinuation. Plasma MDZ area under the curve (AUC) between 2 and 4 h after oral administration in the form of a solution strongly correlated with MDZ clearance. Using this parameter, maximum inhibition of voriconazole and ritonavir was calculated to have occurred only 48 h after starting of the inhibitor (percentage of baseline MDZ clearance, voriconazole: 10.6%; ritonavir: 8.4%). Recovery of CYP3A activity occurred with a half-life of 24 h after voriconazole, whereas ritonavir inhibition was still strong 3 days after discontinuation. These findings underscore the substantial and gradual alterations in dose requirements in the first days of and after such combination therapies.

[Drug interactions]. / Arzneimittelinteraktionen.

Drug-drug interactions can be used to enhance effectiveness but they are also a significant cause of adverse drug reactions. Alterations in liberation, absorption, distribution, metabolism, and excretion may all affect the pharmacokinetics of a drug. Cytochrome P450 enzymes and drug transporters like ABC-transporters determine the clearance of many drugs leading to alterations in therapeutic effect. In contrast pharmacodynamic drug interactions will alter drug effects in the absence of concentration changes of the co-administered drug. Alterations of a drug effect may require changes in dose to maintain the therapeutic effect.

Effect of simultaneous induction and inhibition of CYP3A by St John's Wort and ritonavir on CYP3A activity.

We aimed to assess the effect of coadministration and withdrawal of a potent cytochrome P450 3A (CYP3A) inhibitor (ritonavir) and a potent CYP3A inducer (St John's wort) on CYP3A enzyme activity in an open, fixed-sequence study design. We investigated the pharmacokinetics of midazolam: (i) at baseline, (ii) after a single dose of either St John's wort or ritonavir (each n = 6), (iii) after 14 days of coadministration of ritonavir (300 mg b.i.d.) and St John's wort (300 mg t.i.d.), and (iv) at 2 days after cessation of both St John's wort and ritonavir. Combined administration of inducer and inhibitor resulted in a predominance of enzyme inhibition: coadministration of St John's wort and ritonavir with intravenous administration of midazolam resulted in an increase in the area under the plasma concentration-time curve (AUC)(0-8 h) of midazolam to 180% of baseline value, whereas with orally administered midazolam, the AUC(0-6 h) increased to 412% of baseline value (P < 0.05 for each). After cessation of the coadministered drugs, the AUC(0-6 h) of orally administered midazolam decreased to 6% of the level observed during combined administration, and the AUC(0-8 h) of intravenously administered midazolam decreased to 33% of the values observed during combined administration (P < 0.001 for each). Induction may be unmasked after the withdrawal of a combination of a potent CYP3A inhibitor and a potent CYP3A inducer, leading to substantial drops in drug exposure of CYP3A substrates. This may require substantial dose adjustments, particularly of orally administered drugs.

Calcium balance during calcitriol and paricalcitol administration in healthy humans.

OBJECTIVE: Secondary hyperparathyroidism in hemodialysis patients requires optimal correction of vitamin D deficiency with active vitamin D and analogues. It has been postulated that new vitamin D analogues, i.e. paricalcitol, efficiently suppress parathyroid hormone serum levels (PTH), but do not increase intestinal calcium absorption as much as calcitriol. The effects of calcitriol and paricalcitol on calcium balance can best be characterized under standardized conditions in healthy individuals with normal renal function, because the urinary calcium excretion at steady state corresponds to the net calcium absorption in the gut. METHODS: In a randomized, double-blind, placebo-controlled, 3-way crossover Phase I study in 13 healthy individuals we investigated the changes compared to placebo in PTH and urinary calcium excretion during 6-day treatment periods with paricalcitol (1.5 microg/day) and calcitriol (0.5 microg/day). RESULTS: 24-hour urinary calcium excretion was stable during 6 days of placebo administration. Neither paricalcitol nor calcitriol significantly changed calcium excretion. Urinary creatinine, magnesium and phosphate excretion also remained unchanged over the study periods irrespective of the treatment. However, calcitriol was shown to be effective in reducing iPTH levels during 6 days of treatment (mean reduction 4.03+/-0.69 pmol/l), whereas paricalcitol had no effect. CONCLUSION: Using a dosing ratio of 1:3 for calcitriol:paricalcitol, i.e. the same conversion factor used previously in studies on hemodialysis patients, only calcitriol was able to reduce iPTH levels in healthy individuals. Low-dose calcitriol reduced iPTH levels without raising calcium absorption and without including any hypercalcemia.

Reduction in non-glomerular renal clearance of the caffeine metabolite 1-methylxanthine by probenecid.

OBJECTIVE: Urinary caffeine metabolic ratios used to quantify the activity of numerous drug-metabolizing enzymes are an established component of cocktail approaches for metabolic phenotyping. Because in vitro evidence suggests that 1-methylxanthine (1-MX), a major caffeine metabolite, is actively secreted into urine by organic anion transporters (hOATs), coadministration of renal hOAT inhibitors like probenecid may impair these procedures. METHODS: In a randomized, placebo-controlled, double-blind crossover design, single oral doses of 300 mg caffeine with oral coadministration of placebo or 500 mg probenecid 3 times daily for 2 days were administered to 7 healthy men. The plasma and urine concentrations of caffeine and its major metabolites 1,7-dimethylxanthine (1,7-DMX) and 1-MX were determined by high-performance liquid chromatography. RESULTS: Coadministration of probenecid resulted in a 34% reduction of the renal clearance of 1-MX (mean +/- SD 190 +/- 42 versus 290 +/- 83 ml min(-1), 95% CI on difference 0.2, 200, p = 0.04) with a 41% reduction in its estimated non-glomerular clearance. The renal clearances of caffeine and 1,7-DMX and the area under the plasma concentration-time curves of all substances were not significantly changed. CONCLUSIONS: 1-MX undergoes renal tubular secretion which is substantially reduced by probenecid, possibly due to inhibition of renal hOATs. This inhibition may explain the influence of probenecid on urinary caffeine metabolic ratios and, thus, its impact on the assessment of enzyme activities. It also suggests that 1-MX might serve as a model substrate for the renal tubular transport of organic anions.