The pharmacokinetic study on the interaction between nobiletin and anemarsaponin BII in vivo and in vitro.

CONTEXT: The interaction between nobiletin and anemarsaponin BII could affect the pharmacological activity of these two drugs during their combination. OBJECTIVE: The co-administration of nobiletin and anemarsaponin BII was investigated to explore the interaction and the potential mechanism. MATERIALS AND METHODS: Male Sprague-Dawley rats were only orally administrated with 50 mg/kg nobiletin as the control and another six rats were pre-treated with 100 mg/kg anemarsaponin BII for 7 d followed by the administration of nobiletin. The transport and metabolic stability of nobiletin were evaluated in vitro, and the effect of anemarsaponin BII on the activity of CYP3A4 was also assessed to explore the potential mechanism underlying the interaction. RESULTS: The increasing Cmax (2309.67 ± 68.06 µg/L vs. 1767.67 ± 68.86 µg/L), AUC (28.84 ± 1.34 mg/L × h vs. 19.57 ± 2.76 mg/L × h), prolonged t1/2 (9.80 ± 2.33 h vs. 6.24 ± 1.53 h), and decreased clearance rate (1.46 ± 0.26 vs. 2.42 ± 0.40) of nobilein was observed in rats. Anemarsaponin BII significantly enhanced the metabolic stability of nobiletin in rat liver microsomes (half-life increased from 31.56 min to 39.44 min) and suppressed the transport of nobiletin in Caco-2 cells (efflux rate decreased from 1.57 ± 0.04 to 1.30 ± 0.03). The inhibitory effect of anemarsaponin BII on CYP3A4 was also found with an IC50 value of 10.23 µM. DISCUSSION AND CONCLUSIONS: The interaction between anemarsaponin BII and nobiletin was induced by the inhibition of CYP3A4, which should draw special attention in their clinical co-administration.

Saikosaponins and the deglycosylated metabolites exert liver meridian guiding effect through PXR/CYP3A4 inhibition.

ETHNOPHARMACOLOGICAL RELEVANCE: Radix Bupleuri (RB), traditionally used to treat inflammatory disorders and infectious diseases, represents one of the most successful and widely used herbal drugs in Asia over the past 2000 years. Being realized the role in regulating metabolism and controlling Yin/Yang, RB is not only chosen specifically for treating liver meridian and the corresponding organs, but also believed to have liver meridian guiding property and help potentiate the therapeutic effects of liver. However, the ingredients in RB with liver meridian guiding property and the underly mechanism have not been comprehensively investigated. AIM OF STUDY: Considering the important role of CYP3A4 in first-pass metabolism and the liver exposure of drugs, the present study aimed to determine whether saikosaponins (SSs) and the corresponding saikogenins (SGs) have a role in inhibiting the catalytic activity of CYP3A4 in human liver microsomes and HepG2 hepatoma cells and whether they could suppress CYP3A4 expression by PXR-mediated pathways in HepG2 hepatoma cells. MATERIALS AND METHODS: The effect of SSs and SGs on CYP3A4-mediated midazolam1'-hydroxylation activities in pooled human liver microsomes (HLMs) was first studied. Dose-dependent experiments were performed to obtain the half inhibit concentration (IC50) values. HepG2 cells were used to assay catalytic activity of CYP3A4, reporter function, mRNA levels, and protein expression. The inhibitory effects of SSa and SSd on CYP3A4 activity are negligible, while the corresponding SGs (SGF and SGG) have obvious inhibitory effects on CYP3A4 activity, with IC50 values of 0.45 and 1.30 µM. The similar results were obtained from testing CYP3A4 catalytic activity in HepG2 cells, which correlated well with the suppression of the mRNA and protein levels of CYP3A4. Time-dependent testing of CYP3A4 mRNA and protein levels, as well as co-transfection experiments using the CYP3A4 promoter luciferase plasmid, further confirmed that SSs and SGs could inhibit the expression of CYP3A4 at the transcription level. Furthermore, PXR protein expression decreased in a concentration- and time-dependent manner after cells were exposed to SSs and SGs. PXR overexpression and RNA interference experiments further showed that SSs and SGs down-regulate the catalytic activity and expression of CYP3A4 in HepG2 may be mainly through PXR-dependent manner. CONCLUSION: SSs and SGs inhibit the catalytic activity and expression of CYP3A4 in a PXR-dependent manner, which may be highly related to the liver meridian guiding property of RB.

A case of simvastatin-induced myopathy with SLCO1B1 genetic predisposition and co-ingestion of linagliptin and Stevia rebaudiana.

WHAT IS KNOWN AND OBJECTIVE: SLCO1B1 T521>C variant carriers are susceptible to simvastatin-induced myopathy. We report a patient who developed rhabdomyolysis possibly triggered by a drug-drug and/or herb-drug interaction. CASE DESCRIPTION: A 69-year-old man presented with myalgia and weakness progressing to severe rhabdomyolysis. He had been taking 40 mg simvastatin daily for 10 years and recently consumed supplements, including Stevia rebaudiana and linagliptin. Genotyping revealed he carried one copy of SLCO1B1 T521>C and two copies of ABCG2 C421>A. WHAT IS NEW AND CONCLUSION: Despite apparent long-term safe administration, co-ingestion of simvastatin and other CYP3A4 inhibitors may result in severe myopathy in those at increased genetic risk.

Miopatía por estatinas y vitamina D / Statin-Related Myopathy and Vitamin D

Las estatinas son fármacos habitualmente seguros y bien tolerados, muy eficaces para la prevención de trastornos cardiovasculares. La presencia de mialgias, poco frecuente, pero con incidencia dispar en diversos reportes, es una de las causas de abandono de su uso. También las distintas denominaciones (mialgia, miopatía, rabdomiólisis) y la subjetividad de cada paciente para referirlas han creado confusión en el tema. Se ha comenzado a reportar asociación entre niveles de vitamina D sérica disminuida y mayor riesgo de miopatía, por un lado, y trabajos donde pacientes que las abandonaban a causa de mialgias, con deficiencia de vitamina D, pueden tolerarlas una vez que se suplementa la vitamina hasta valores deseables. La presencia de polimorfismos en genes de enzimas que metabolizan o transportan a las estatinas es otro factor claramente relacionado con miopatía. Es posible que el déficit de vitamina D deba ser considerado un factor de riesgo para desarrollar miopatía por estatinas, como lo serían también la administración simultánea de fármacos que se metabolizan por la misma vía de citocromo P450, o la presencia de los polimorfismos mencionados. En conclusión, el hallazgo de tener deficiencia de vitamina D se asocia a miopatía por estatinas, o que es un factor de riego para desarrollarla, abre nuevas perspectivas para un gran número de pacientes que abandonan este tratamiento debido a esta patología. (AU)

Statins are usually safe and well tolerated drugs, very effective for preventing cardiovascular complications. The rare presence of myalgia, with different incidence as reported by several studies, is one of the causes of lack of drug compliance. Also the different symptoms referred (myalgia, myopathy, rhabdomyolysis) and the lack of objetivity of each patient when referring to the symptoms, have created confusion in this matter. Associations between decreased vitamin D levels and increased risk of myopathy has been reported. Indeed, studies describing patients with vitamin D deficiency who are not compliant due to myalgia show that they become tolerant to the drugs once the vitamin is supplemented to desirable values. The presence of gene polymorphisms for enzymes that metabolize or transport statins is another factor clearly related to myopathy. Therefore, we should consider vitamin D deficiency and other conditions such as the simultaneous administration of drugs that are metabolized by the same cytochrome P450 pathway, or the presence of mentioned polymorphisms as a risk factor for developing myopathy due to statins. In conclusion, the finding that vitamin D deficiency is associated with statin myopathy, or is a risk factor its develpoment, opens new perspectives for a large number of patients who leave this treatment due to this condition. (AU)

Effect of Cinnamomum cassia on the Pharmacokinetics and Pharmacodynamics of Pioglitazone.

BACKGROUND: Millions of people today use herbs either as food or in the form of medicine along with other medications. Many of the herbs can interact with these medications, causing either potentially dangerous side effects or improved or reduced benefits from the medication. OBJECTIVE: The present study was performed to determine the influence of cinnamon, on the pharmacokinetics and pharmacodynamics of pioglitazone. METHOD: Studies were conducted in normal and alloxan induced diabetic rats and rabbits with oral administration of selected doses of pioglitazone, cinnamon and their combination. Blood samples were collected at regular intervals of time and were analysed for glucose by GOD/POD method and for pioglitazone by HPLC method respectively. Body weights were also measured every week. RESULTS: Significant differences were seen in pharmacokinetic parameters of pioglitazone like AUC, t1/2, Ke, Cl/F, Vd/F when given in combination with cinnamon in normal and diabetic rabbits. The combination of pioglitazone and cinnamon was found to reduce the glucose levels and body weights significantly than pioglitazone. The results indicating increased AUC of pioglitazone on pretreatment with cinnamon suggest an interaction indicating decreased metabolism of pioglitazone as a result of CYP 3A4 inhibition and thereby producing a potentiating effect. CONCLUSION: Cinnamon enhanced the bioavailability of pioglitazone by inhibiting the CYP3A4 enzyme. Hence, cinnamon might be beneficial when used in combination with pioglitazone in diabetic patients and an adjustment of dose of pioglitazone may be necessary.

Preclinical assessment of the interactions between the antiretroviral drugs, ritonavir and efavirenz, and the tyrosine kinase inhibitor erlotinib.

PURPOSE: Prevalence of non-AIDS-defining cancers (NADCs) has increased in the era of potent antiretroviral treatments. Incidence rates of NADCs now exceed AIDS-defining cancers in HIV-positive patients. Treatment of NADCs may be complicated by interactions between antiretrovirals and chemotherapy mostly via inhibition or induction of CYP3A4. Erlotinib is used to treat non-small cell lung and pancreatic cancer and is primarily metabolized by CYP3A4 into multiple products including the active metabolite (OSI-420). Preclinical in vivo assessment was performed to gain a better understanding of CYP3A4-mediated interactions between antiretrovirals and erlotinib. METHODS: Erlotinib (50 mg/kg p.o.) was administered to male FVB mice in the presence and absence of dexamethasone (10 mg/kg p.o. QDx4), efavirenz (25 mg/kg p.o. QDx4), ketoconazole (50 mg/kg p.o.), or ritonavir (12.5 mg/kg p.o.). Blood samples were collected to characterize exposure (AUC). RESULTS: Administration of erlotinib with CYP3A4 inducers (dexamethasone) and inhibitors (ketoconazole and ritonavir) resulted in significant alterations in erlotinib exposure. Ketoconazole and ritonavir resulted in a 1.7- and 3.0-fold increase in erlotinib AUC, respectively, while dexamethasone results in a 0.6-fold decrease in erlotinib AUC. The CYP3A4 inducer efavirenz did not have a significant effect on erlotinib exposure. CONCLUSION: CYP3A4 inducers and inhibitors altered the exposure of erlotinib. Until a definitive clinical trial is performed, erlotinib should be used with caution in patients on a ritonavir-containing antiretroviral regimen, while standard doses may be appropriate for patients on an efavirenz-containing antiretroviral regimen.