Glycyrrhizin protects against diosbulbin B-induced hepatotoxicity by inhibiting the metabolic activation of diosbulbin B.

Diosbulbin B (DIOB), isolated from herbal medicine Dioscorea bulbifera L. (DB), could induce severe liver injury, and its toxicology was closely associated with CYP3A4-mediated metabolic oxidation of furan moiety to the corresponding cis-enedial reactive metabolite. Glycyrrhizin (GL), the major bioactive ingredient in licorice, can inhibit the activity of CYP3A4. Thus, GL may ameliorate hepatotoxicity of DIOB when GL and DIOB are co-administrated. The study aimed to investigate the protective effect of GL on DIOB-induced hepatotoxicity and the underlying mechanism. Biochemical and histopathological analysis demonstrated that GL alleviated DIOB-induced hepatotoxicity in a dose-dependent manner. In vitro study with mouse liver microsomes (MLMs) demonstrated that GL reduced the formation of metabolic activation-derived pyrrole-glutathione (GSH) conjugates from DIOB. Toxicokinetic studies showed that the pretreatment with GL caused the increase of AUCs and Cmax of DIOB in blood of mice, resulting in accelerating the accumulation of DIOB in the circulation. In addition, the pretreatment with GL alleviated DIOB-induced hepatic GSH depletion. In summary, GL ameliorated DIOB-induced hepatotoxicity, possibly related to the inhibition of the metabolic activation of DIOB. Thus, development of a standardized combination of DIOB with GL may protect patients from DIOB-induced liver injury.

Glycyrrhetinic acid ameliorates diosbulbin B-induced hepatotoxicity in mice by modulating metabolic activation of diosbulbin B.

Exposure to diosbulbin B (DBB), the primary component of the herbal medicine Dioscorea bulbifera L. (DB), can cause liver injury in humans and experimental animals. A previous study found DBB-induced hepatotoxicity was initiated by CYP3A4-mediated metabolic activation and subsequent formation of adducts with cellular proteins. The herbal medicine licorice (Glycyrrhiza glabra L.) is frequently combined with DB used in numerous Chinese medicinal formulas in an effort to protect against DB-elicited hepatotoxicity. Importantly, glycyrrhetinic acid (GA), the major bioactive ingredient in licorice, inhibits CYP3A4 activity. The study aimed to investigate the protection of GA against DBB-induced hepatotoxicity and the underlying mechanism. Biochemical and histopathological analysis showed GA alleviated DBB-induced liver injury in a dose-dependent manner. In vitro metabolism assay with mouse liver microsomes (MLMs) indicated that GA decreased the generation of metabolic activation-derived pyrrole-glutathione (GSH) conjugates from DBB. Toxicokinetic studies demonstrated that GA increased maximal serum concentration (Cmax ) and area under the serum-time curve (AUC) of DBB in mice. In addition, GA attenuated hepatic GSH depletion caused by DBB. Further mechanistic studies showed that GA reduced the production of DBB-derived pyrroline-protein adducts in a dose-dependent manner. In conclusion, our findings demonstrated that GA exerted protective effect against DBB-induced hepatotoxicity, mainly correlated with suppressing the metabolic activation of DBB. Therefore, the development of a standardized combination of DBB with GA may protect patients from DBB-induced hepatotoxicity.

Cannabinoid Poisoning by Hemp Seed Oil in a Child.

We report a case of mild cannabinoid poisoning in a preschool child, after 3-week ingestion of hemp seed oil prescribed by his pediatrician to strengthen his immune system. The patient presented neurological symptoms that disappeared after intravenous hydration. A possible mild withdrawal syndrome was reported after discharge. The main metabolite of Δ-tetrahydrocannabinol was detected in urine, and very low concentration of Δ-tetrahydrocannabinol was detected in the ingested product. This is, as far as we know, the first report of cannabinoid poisoning after medical prescription of hemp seed oil in a preschool child.

[Direct oral anticoagulant, useful pharmacological characteristics in clinical practice]. / Données pharmacologiques utiles pour une bonne utilisation des anticoagulants oraux directs.

Direct oral anticoagulants offer an alternative to vitamin K antagonist drugs in the prevention and treatment of thromboembolic events. Unlike the latter, they inhibit directly and specifically coagulation factors (Xa, IIa). Their pharmacological properties allow a fixed dose administration and no biological monitoring for the majority of patients. However, their pharmacokinetics dependent of membrane transporters (P-gp) and cytochrome P450 (CYP3A4) expose them to significant drug-drug interactions. Dose adjustment may then become necessary as in some clinical situations, such as kidney and liver failure. However, some questions remain open, particularly on the optimal handling of these molecules in some population (elderly patients, renal and hepatic impairment or polymedicated).

Paracetamol and simvastatin: a potential interaction resulting in hepatotoxicity.

The safety profile of paracetamol and simvastatin is sufficiently well known, although no interactions between these two medicinal products have been described in the scientific literature so far. A 66-year-old female patient who experienced myocardial infarction and underwent coronary artery bypass grafting 9 years ago was taking simvastatin at a daily dose of 10 mg. Liver enzyme tests were carried out regularly, and their results were always normal. Later on, the patient took 6 tablets of fixed combination medicinal product Gripex(TM) (paracetamol, pseudoephedrine, and dextromethorphan) per day due to a fever. The daily dose of paracetamol taken by the patient totaled 1.95 g. The patient developed severe jaundice, nausea, vomiting; blood bilirubin levels increased more than 3 times; alanine transaminase, more than 10 times; and asparagine transaminase, more than 5 times. Paracetamol is metabolized by CYP enzymes (CYP2E1, 1A2, 2A6, 3A4) to a reactive metabolite, N-acetyl-p-benzoquinone-imine (NAPQI). Under conditions of excessive NAPQI formation or reduction in glutathione stores by approximately 70%, NAPQI covalently binds to the cysteinyl sulfhydryl groups of cellular proteins, forming NAPQI-protein adducts. Simvastatin is a substrate of CYP3A4 enzyme. Clinical and pharmacological data, available in the published literature, allow the assumption that simvastatin may induce CYP3A4 and result in increased hepatoxicity of paracetamol.

Docetaxel metabolism is not altered by imatinib: findings from an early phase study in metastatic breast cancer.

Docetaxel is primarily metabolized by CYP3A4 and susceptible to alterations in clearance by CYP3A4 inhibition and induction. Imatinib is a CYP3A4 inhibitor. A phase I study of docetaxel and imatinib in metastatic breast cancer (MBC) was conducted to test the hypothesis that imatinib decreased docetaxel clearance. Docetaxel was administered weekly × 3 with daily imatinib, repeated every 28 days; during cycle 1, imatinib was started on day 8. Docetaxel and imatinib pharmacokinetics, and hepatic CYP3A4 activity (erythromycin breath test) were evaluated during cycles 1 and 2. Toxicity and efficacy were assessed. Twelve patients were enrolled to three docetaxel/imatinib dose levels: 20 mg/m(2)/600 mg (DL1), 25 mg/m(2)/600 mg (DL2), and 25 mg/m(2)/400 mg (DL2a). Median number of prior chemotherapy regimens was 2 (range, 0-8). Toxicities were primarily observed at DL2; dose-limiting toxicities were Grade 3 transaminase elevations and diarrhea, and 5 patients had grade 2 nausea. Two patients had partial responses (7 months); two stable disease (2 and 4 months); five had progressive disease. Despite a 42% decrease in CYP3A4 activity after 3 weeks of imatinib co-administration, docetaxel clearance was unchanged. Mean ± standard deviation steady-state imatinib trough concentration (2.6 ± 1.2 µg/ml) was approximately 2.6-fold higher than previously observed in other cancer populations, and likely contributed to the poor tolerability of the combination in MBC. In conclusion, imatinib inhibited CYP3A4 but did not affect docetaxel clearance. Clinically, further investigation of this combination in MBC is not warranted due to excessive toxicities. However, these unexpected pharmacokinetic findings support further investigation of mechanisms underlying docetaxel elimination pathways.

A phase I evaluation of the combination of vinflunine and erlotinib in patients with refractory solid tumors.

PURPOSE: Epidermal growth factor receptor (EGFR) inhibition may overcome chemotherapy resistance by inhibiting important anti-apoptotic signals that are constitutively activated by an overstimulated EGFR pathway. METHODS: This phase I dose escalation trial assessed the safety and efficacy of vinflunine, a novel vinca alkaloid microtubule inhibitor, with erlotinib, an EGFR tyrosine kinase inhibitor, in patients with refractory solid tumors. RESULTS: Seventeen patients were treated, 10 with continuous erlotinib, and 7 with intermittent erlotinib. At dose level 1, vinflunine 280 mg/m(2) IV day 1 and erlotinib 75 mg PO days 2-21 ("continuous erlotinib") in 21 day cycles, two of four patients experienced DLTs. At dose level -1 (vinflunine 250 mg/m(2) every 21 days and erlotinib 75 mg/day), two of six patients experienced DLTs. The study was amended to enroll to "intermittent erlotinib" dosing: vinflunine day 1 and erlotinib days 2-15 of a 21 day cycle. Two of seven experienced DLTs and the study was terminated. One patient with breast cancer had a partial response; three had stable disease ≥ 6 cycles. All were treated in the continuous erlotinib group. CONCLUSIONS: Given the marked toxicity in our patient population, the combination of vinflunine and erlotinib cannot be recommended for further study with these dosing schemas.

Reversible parkinsonism and cognitive decline due to a possible interaction of valproic acid and quetiapine.

WHAT IS KNOWN AND OBJECTIVE: Combination therapy with valproic acid plus quetiapine is recommended as one of the first-line approaches to treatment of manic or mixed episodes in patients with bipolar disorder. CASE SUMMARY: A 66-year-old patient with this psychiatric disease developed parkinsonism and cognitive decline during concomitant treatment with both drugs. The rapid onset of symptoms soon after use of the combination suggested an interaction/using the Karch-Lasagna criteria, the interaction was judged to be definite. WHAT IS NEW AND CONCLUSION: Their evidence on a pharmacokinetic drug interaction between the two drugs is conflicting but possible underlying mechanisms proposed include CYP3A4 inhibition. As concomitant use of valproate and quetiapine is now quite frequent in bipolar disorder, this potential interaction should be closely monitored, especially in the elderly.

CYP3A4-Mediated oxygenation versus dehydrogenation of raloxifene.

Raloxifene was approved in 2007 by the FDA for the chemoprevention of breast cancer in postmenopausal women at high risk for invasive breast cancer. Approval was based in part on the improved safety profile for raloxifene relative to the standard treatment of tamoxifen. However, recent studies have demonstrated the ability of raloxifene to form reactive intermediates and act as a mechanism-based inhibitor of cytochrome P450 3A4 (CYP3A4) by forming adducts with the apoprotein. However, previous studies could not differentiate between dehydrogenation to a diquinone methide and the more common oxygenation pathway to an arene oxide as the most likely intermediate to inactivate CYP3A4. In the current work, (18)O-incorporation studies were utilized to carefully elucidate CYP3A4-mediated oxygenation versus dehydrogenation of raloxifene. These studies established that 3'-hydroxyraloxifene is produced exclusively via CYP3A4-mediated oxygenation and provide convincing evidence for the mechanism of CYP3A4-mediated dehydrogenation of raloxifene to a reactive diquinone methide, while excluding the alternative arene oxide pathway. Furthermore, it was demonstrated that 7-hydroxyraloxifene, which was previously believed to be a typical O(2)-derived metabolite of CYP3A4, is in fact produced by a highly unusual hydrolysis pathway from a putative ester, formed by the conjugation of raloxifene diquinone methide with a carboxylic acid moiety of CYP3A4, or other proteins in the reconstituted system. These findings not only confirm CYP3A4-mediated dehydrogenation of raloxifene to a reactive diquinone methide but also suggest a novel route of raloxifene toxicity.

[Methyldopa-induced acute reactive hepatitis in pregnancy, drug-metabolizing capacity of the liver]. / Methyldopa által indukált akut reaktív hepatitis terhességben, a máj gyógyszer-metabolizáló képességének alakulása.

Alpha-methyldopa is a regularly used antihypertensive drug during pregnancy. Methyldopa, which decreases the sympathoadrenal system, is the first drug of choice since decades. The reactive hepatitis is not frequent, but known serious side effect of alpha-methyldopa. In non-pregnant women the estimated rate of manifest hepatotoxicity is 2.5-10%. In our case, gestation hypertension developed at the 21st gestation week of a 35 year-old pregnant woman. Oral methyldopa, a central alpha adrenergic blocker therapy was introduced. On the 23rd gestation week acute hepatitis developed. During differential diagnosis of hepatitis, the etiology of methyldopa was taken into account. Viral and autoimmune origin was rolled out. No fetal aberration was found during ultrasound examination. The function of drug metabolizing function from blood was measured by CYP phenotyping (CYP gene expression analysis). CYP3A4 enzyme plays a primary role in the metabolism of nifedipine. Antihypertensive therapy was changed from methyldopa to nifedipine. Nifedipine dosage was based on the value of CYP3A4 gene expression. With the reduced nifedipine therapy (30 mg daily), blood pressure was successfully under control. The diagnosis of alpha-methyldopa induced hepatitis was based on anamnesis, clinical picture and the results of chemical and radiological examination and confirmed by the level of drug-metabolizing capacity. The gestation hepatotoxicity of alpha-methyldopa was reported first in 1969 by Elkington Smith, who suggested the monitoring of serum aminotransferase during alpha-methyldopa therapy in pregnancy in their case report. Our case report confirms that monitoring of serum aminotransferase level is still valuable when treating a pregnant woman with alpha-methyldopa.

Physiologically-Based Pharmacokinetic Modeling for the Prediction of a Drug-Drug Interaction of Combined Effects on P-glycoprotein and Cytochrome P450 3A.

Direct oral anticoagulants, such as apixaban and rivaroxaban, are important for the treatment and prophylaxis of venous thromboembolism and to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Because apixaban and rivaroxaban are predominantly eliminated by cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp), concomitant use of combined P-gp and strong CYP3A4 inhibitors and inducers should be avoided. Physiologically-based pharmacokinetic models for apixaban and rivaroxaban were developed to estimate the net effect of CYP3A induction, P-gp inhibition, and P-gp induction by rifampicin. The disposition of rivaroxaban is more complex compared with apixaban because both hepatic and renal P-gp is considered to contribute to rivaroxaban elimination. Furthermore, organic anion transporter-3, a renal uptake transporter, may also contribute the elimination of rivaroxaban from systemic circulation. The models were verified with observed clinical drug-drug interactions with CYP3A and P-gp inhibitors. With the developed models, the predicted area under the concentration time curve and maximum concentration ratios were 0.43 and 0.48, respectively, for apixaban, and 0.50-0.52 and 0.72-0.73, respectively, for rivaroxaban when coadministered with 600 mg multiple doses of rifampicin and that were very close to observed data. The impact of each of the elimination pathways was assessed for rivaroxaban, and inhibition of CYP3A led to a larger impact over intestinal and hepatic P-gp. Inhibition of renal organic anion transporter-3 or P-gp led to an overall modest interaction. The developed apixaban and rivaroxaban models can be further applied to the investigation of interactions with other P-gp and/or CYP3A4 inhibitors and inducers.

[Pharmacokinetics and pharmacodynamics of the new oral anticoagulants dabigatran and rivaroxaban]. / Farmacocinética y farmacodinamia de los nuevos anticoagulantes orales.

Dabigatran is the first available oral direct thrombin inhibitor anticoagulant. Absorption of the prodrug, dabigatran etexilate and its conversion to dabigatran is rapid (peak plasma concentrations are reached 4-6 hours following surgery, and a further 2 hours later). Its oral bioavailability is low, but shows reduced interindividual variability. Dabigatran specifically and reversibly inhibits thrombin, the key enzyme in the coagulation cascade. Studies both in healthy volunteers and in patients undergoing major orthopaedic surgery show a predictable pk/pd profile that allows for fixed-dose regimens. The anticoagulant effect correlates adequately with the plasma concentrations of the drug, demonstrating effective anticoagulation combined with a low risk of bleeding. Dabigatran is mainly eliminated by renal excretion (a fact which affects the dosage in elderly and in moderate-severe renal failure patients), and no hepatic metabolism by cytochrome P450 isoenzymes has been observed, showing a good interaction profile. Rivaroxaban will probably be the first available oral factor Xa (FXa) direct inhibitor anticoagulant drug. It produces a reversible and predictable inhibition of FXa activity with potential to inhibit clot-bound FXa. Its pharmacokinetic characteristics include rapid absorption, high oral availability, high plasma protein binding and a half-life of aprox. 8 hours. Rivaroxaban elimination is mainly renal, but also through faecal matter and by hepatic metabolism. Although the drug has demonstrated moderate potential to interact with strong CYP3A4 inhibitors, it does not inhibit or induce any major CYP450 enzyme.

Avascular Necrosis of the Femoral Head.

About 250000 patients are operated on annually for hip arthroplasty in the USA alone. Of this number, about 10% the cause of their osteoarthritis is the avascular necrosis of the femoral head. But the causes of necrosis are multiple and many of them are still unknown. That is why small advances in etiopathogenesis, diagnosis and treatment of different causes are very important in order to reduce the number of affected patients. It may seem that small changes, studies focused on the details of different diseases do not bring great changes to science, but it is these small changes that end up adding great evolutions in our knowledge. In addition, the changes of recent years, are not focused on our specialty in technical or anatomical evolutions exclusively, but are often based on biological bases, which is the branch that evolves more within trauma and orthopedics. That is why open and constant minds are what help us move forward.

Time course of the increase in 4beta-hydroxycholesterol concentration during carbamazepine treatment of paediatric patients with epilepsy.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: CYP3A4 converts cholesterol into 4beta-hydroxycholesterol. We have suggested that 4beta-hydroxycholesterol could be used as a clinical marker for CYP3A4 activity aiding in dose adjustments. The kinetics of 4beta-hydroxycholesterol formation is not known, however, and must be determined in order to establish under what conditions 4beta-hydroxycholesterol can be used as a CYP3A marker. WHAT THIS STUDY ADDS: The concentration of 4beta-hydroxycholesterol increases very slowly during CYP3A4/5 induction in paediatric patients. Whereas induction of CYP3A4/5 was apparently complete within 1-2 weeks of carbamazepine treatment, plasma 4beta-hydroxycholesterol levels continued to increase until at least 8 weeks of treatment. AIMS To investigate the time course of the increase in 4beta-hydroxycholesterol and carbamazepine plasma concentrations during treatment of paediatric patients with epilepsy. METHODS: Eight paediatric patients with newly diagnosed epilepsy were studied. Blood samples were drawn before and after about 1, 2, 4, 8 and 16 weeks of carbamazepine treatment. The plasma concentrations of 4beta-hydroxycholesterol were determined by gas chromatography-mass spectrometry and carbamazepine and its epoxide metabolite by high-performance liquid chromatography. RESULTS: The basal plasma concentrations of 4beta-hydroxycholesterol showed a large range of observed values between 18 and 99 ng ml(-1). Carbamazepine treatment increased mean plasma 4beta-hydroxycholesterol significantly already after 1 week of treatment (from 43 to 80 ng ml(-1), P < 0.001). 4beta-Hydroxycholesterol concentrations continued to increase until at least 8 weeks of treatment and the concentrations in the final samples (8-23 weeks of treatment) varied between 122 and 494 ng ml(-1). Plasma concentrations of carbamazepine and its epoxide metabolite reached steady state at 1-2 weeks after last dose change. CONCLUSIONS: Carbamazepine treatment of paediatric patients with epilepsy resulted in an induction of CYP3A4/5 and a concomitant increase in plasma 4beta-hydroxycholesterol. Whereas the induction of CYP3A4/5 was apparently complete after 1-2 weeks, the increase in 4beta-hydroxycholesterol continued for several weeks. Thus CYP3A4 activity is not the only determinant of the circulating level of 4beta-hydroxycholesterol. Additional factors such as transport and storage or presence of another enzyme may thus be of importance.

Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy.

Ketamine is a phencyclidine derivative, which functions primarily as an antagonist of the N-methyl-D-aspartate receptor. It has no affinity for gamma-aminobutyric acid receptors in the central nervous system. Ketamine shows a chiral structure consisting of two optical isomers. It undergoes oxidative metabolism, mainly to norketamine by cytochrome P450 (CYP) 3A and CYP2B6 enzymes. The use of S-ketamine is increasing worldwide, since the S(+)-enantiomer has been postulated to be a four times more potent anesthetic and analgesic than the R(-)-enantiomer and approximately two times more effective than the racemic mixture of ketamine. Because of extensive first-pass metabolism, oral bioavailability is poor and ketamine is vulnerable to pharmacokinetic drug interactions. Sublingual and nasal formulations of ketamine are being developed, and especially nasal administration produces rapid maximum plasma ketamine concentrations with relatively high bioavailability. Ketamine produces hemodynamically stable anesthesia via central sympathetic stimulation without affecting respiratory function. Animal studies have shown that ketamine has neuroprotective properties, and there is no evidence of elevated intracranial pressure after ketamine dosing in humans. Low-dose perioperative ketamine may reduce opioid consumption and chronic postsurgical pain after specific surgical procedures. However, long-term analgesic effects of ketamine in chronic pain patients have not been demonstrated. Besides analgesic properties, ketamine has rapid-acting antidepressant effects, which may be useful in treating therapy-resistant depressive patients. Well-known psychotomimetic and cognitive adverse effects restrict the clinical usefulness of ketamine, even though fewer psychomimetic adverse effects have been reported with S-ketamine in comparison with the racemate. Safety issues in long-term use are yet to be resolved.

Evaluation of the potential for pharmacokinetic drug-drug interaction between armodafinil and carbamazepine in healthy adults.

PURPOSE: Polypharmacy is common in psychiatry practice and can lead to an increased risk of drug interactions. Armodafinil, a wakefulness-promoting agent, has been studied as adjunctive therapy for the treatment of major depressive episodes associated with bipolar I disorder. Armodafinil and the mood stabilizer carbamazepine are both inducers of and substrates for cytochrome P450 (CYP3A4). This study was designed to evaluate the bidirectional carbamazepine-armodafinil pharmacokinetic drug-drug interaction. METHODS: This was an open-label, single-center study conducted in healthy adult men. Subjects assigned to group 1 received a dose of carbamazepine (200 mg) alone and a dose after pretreatment with daily dosing of armodafinil (titrated to 250 mg/d). Subjects assigned to group 2 received a dose of armodafinil (250 mg) alone and a dose after pretreatment with carbamazepine BID (titrated to 400 mg/d). Pharmacokinetic parameters for carbamazepine, armodafinil, and their major circulating metabolites were determined when dosed alone and after pretreatment with the other drug. The safety and tolerability of armodafinil and carbamazepine were also assessed throughout the study. FINDINGS: Eighty-one subjects enrolled in the study (group 1 = 40; group 2 = 41), of whom 79 (group 1 = 40; group 2 = 39) were evaluable for pharmacokinetic analysis and 80 (group 1 = 40; group 2 = 40) were evaluable for safety analysis. In group 1, pretreatment with armodafinil reduced systemic exposure to carbamazepine by 12% for Cmax and 25% for AUC (based on comparison of geometric means). Similarly, in group 2, pretreatment with carbamazepine reduced systemic exposure to armodafinil by 11% for Cmax and 37% for AUC. Systemic exposure to the metabolites of these agents that are formed via CYP3A4 were increased after pretreatment in each group. There were no new or unexpected adverse events. IMPLICATIONS: Systemic exposure to both carbamazepine and armodafinil was reduced after pretreatment with the other drug; systemic exposure to the metabolites of each drug, which are formed via CYP3A4, was increased. These changes were consistent with the induction of CYP3A4. Both drugs were generally safe and well tolerated alone and in combination under the conditions studied. Dose adjustment may be required when initiating or discontinuing armodafinil and carbamazepine cotherapy.

Pharmacodynamic profile and drug interactions with non-vitamin K antagonist oral anticoagulants: implications for patients with atrial fibrillation.

INTRODUCTION: Non-vitamin K antagonist oral anticoagulants (NOACs) have been developed to prevent ischemic stroke and systemic thromboembolism in patients with nonvalvular atrial fibrillation. Owing to their predictable pharmacological profiles, they can be given in fixed doses without the need for routine coagulation monitoring. However, their distinctive pharmacological properties also raise issues about potential drug interactions. AREAS COVERED: A literature search was conducted to extract published studies on the pharmacodynamics and drug interactions involving NOACs. Available data from US FDA and European Medicine Agency were also included. As these agents are substrates of permeability glycoprotein (P-gp) efflux transporter and/or CYP3A4 enzymes, articles focusing on the co-administration of NOACs and drugs affecting these pathways are discussed. Concomitant use of NOACs with antiplatelet agents may potentially increase bleeding risk. EXPERT OPINION: Measurement of anticoagulant effects is desired to evaluate the risk of thromboembolism or bleeding for patients with NOACs. Prescribers should be vigilant against combination prescription of NOACs with strong inhibitors (such as ketoconazole) or inducers of P-gp and/or CYP3A4 (such as rifampicin). Potential benefit of concurrent use of these agents with antiplatelet drugs should be cautiously balanced against latent risk in specific clinical situations.

Effects of hormonal contraception on antiretroviral drug metabolism, pharmacokinetics and pharmacodynamics.

Among women, human immunodeficiency virus type 1 (HIV-1) infection is most prevalent in those of reproductive age. These women are also at risk of unintended or mistimed pregnancies. Hormonal contraceptives (HCs) are one of the most commonly used methods of family planning worldwide. Therefore, concurrent use of HC among women on antiretroviral medications (ARVs) is increasingly common. ARVs are being investigated and have been approved for pre-exposure prophylaxis (PrEP), and therefore, drug-drug interactions must also be considered in HIV-1-negative women who want to prevent both unintended pregnancy and HIV-1 infection. This article will review four main interactions: (i) the effect of HCs on ARV pharmacokinetics (PK) and pharmacodynamics (PD) during therapy, (ii) the effect of ARVs on HC PK and PD, (iii) the role of drug transporters on drug-drug interactions, and (iv) ongoing research into the effect of HCs on pre-exposure prophylaxis PK and PD.

Cytochrome P450 drug interactions with statin therapy.

Statins are commonly used in the treatment of hyperlipidaemia. Although the benefits of statins are well-documented, they have the potential to cause myopathy and rhabdomyolysis due to the complex interactions of drugs, comorbidities and genetics. The cytochrome P450 family consists of major enzymes involved in drug metabolism and bioactivation. This article aims to highlight drug interactions involving statins, as well as provide updated recommendations and approaches regarding the safe and appropriate use of statins in the primary care setting.

Effects of pravastatin on the pharmacokinetic parameters of nimodipine after oral and intravenous administration in rats: possible role of CYP3A4 inhibition by pravastatin.

OBJECTIVE: The aim of this study was to investigate the effects of pravastatin on the pharmacokinetics of nimodipine in rats. MATERIALS AND METHODS: The effect of pravastatin on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4 activity was evaluated. Nimodipine was administered to rats intravenously (3 mg/kg) and orally (12 mg/kg) with pravastatin (0.3 and 1 mg/kg). RESULTS: Pravastatin inhibited CYP3A4 enzyme activity in a concentration-dependent manner with a 50% inhibition concentration (IC(50)) of 14 µM. Compared with the oral control group, the area under the plasma concentration-time curve (AUC(0-∞)) of nimodipine was increased significantly. Consequently, the absolute bioavailability (AB) of nimodipine with pravastatin (1 mg/kg) was 31.1%, which was significantly enhanced compared with the oral control group. Moreover, the relative bioavailability (RB) of nimodipine was 1.12- to 1.31-fold greater than that of the control group. CONCLUSIONS: The enhanced oral bioavailability of nimodipine might be mainly due to inhibition of the CYP3A-mediated metabolism of nimodipine in the small intestine and/or in the liver and due to reduction of the total body clearance rather than both to inhibition of the P-gp efflux transporter in the small intestine and reduction of renal elimination of nimodipine by pravastatin. The increase in the oral bioavailability of nimodipine with pravastatin should be taken into consideration of potential drug interactions between nimodipine and pravastatin.