Orally co-administrated oleo-gum resin of Commiphora myrrha decreases the bioavailability of cyclosporine A in rats.

Cyclosporine A is a narrow therapeutic indexed immunosuppressant used after organ transplantation. Several herbs have been reported to alter its pharmacokinetics. Myrrh, dried oleogum resin obtained from Commiphora myrrha (Burseraceae) has been used for many common ailments. The present study was carried out to investigate the effect of myrrh on the pharmacokinetics of cyclosporine A. The rats of the control group received 60 mg/kg, p.o. cyclosporine A, and blood samples were collected at predetermined time intervals. Rats of the test group were treated with an aqueous suspension of myrrh (380 mg/kg p.o.) for eight days and on 8th day a single dose of cyclosporine A was administered to the treated group after 1 h of myrrh administration. Blood samples were drawn at predetermined time points and the drug was analyzed in whole blood by using H-Class UPLC-TQD. Pharmacokinetic profiles of control and test group were compared. Statistically significant differences were observed between the pharmacokinetic parameters of control and treated groups. In the myrrh treated group, the AUC(0-t) and C(max) of cyclosporine A was decreased by about 45% and 48%, respectively. The time to reach maximum concentration (T(max)) remained almost unchanged in both groups. Results indicated that the bioavailability of cyclosporine A was reduced by about 45% when co-administered with myrrh. This observation suggests that concurrent consumption of myrrh and cyclosporine A should be avoided. To confirm the clinical relevance of these findings, P-gp and CYP3A based molecular investigations can be performed along with a well-planned clinical study.

Investigating the Potential Effect of Commiphora myrrha on the Pharmacokinetics of Theophylline, a Narrow Therapeutic Index Drug.

AIM: The present study was conducted to investigate the effect of commonly used herb Commiphora myrrha on the pharmacokinetic profile of theophylline (narrow therapeutic index drug) in rabbits. METHODS: In the experimental groups, theophylline (16 mg/kg) was given orally to the rabbits. Where aqueous saline suspension of Commiphora myrrha (176 mg/kg, p.o.), was given to the rabbits and the blood samples were withdrawn at different time intervals (0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 36 h) from marginal ear vein after dosing and theophylline in plasma was analyzed by HPLC method. RESULTS: It was observed that there a significant differences in the Cmax, AUC, AUMC, t1/2, and MRT of theophylline when coadministered with Commiphora myrrha which indicate that the herb affect the metabolism and elimination when coadministered with theophylline. CONCLUSION: Our results suggested that concurrent use of investigated herb alters the pharmacokinetics of theophylline. Confirmation of these results in human studies will warrant changes in theophylline dose or frequency when coadministered with herb under consideration.

Impact of Herbal Medicines like Nigella sativa, Trigonella foenum-graecum, and Ferula asafoetida, on Cytochrome P450 2C11 Gene Expression in Rat Liver.

AIM: Combined use of herbs and drugs may result in clinically important herb-drug interactions. The majorities of these interactions are thought to be metabolism-based and involve induction or inhibition of cytochrome P450 (CYP). The current study was designed to investigate the effect of some commonly used herbs on rat CYP2C11 gene expression and metabolic activity. METHODS: Wistar rats were treated for 7 days with increasing doses of 3 herbs; Nigella sativa, Trigonella foenum-graecum, and Ferula asafoetida. Thereafter, CYP2C11 mRNA and protein levels were determined by real-time polymerase chain reaction (RT-PCR) and western blot analyses, respectively. In vitro metabolic activity of CYP2C11 was performed on rat hepatic microsomes using tolbutamide as specific substrate. RESULTS: Our results showed that all the 3 herbs significantly inhibited the mRNA and protein expression levels of CYP2C11 in a dose-dependent manner. Furthermore, the in vitro enzyme metabolic activity study showed a significant decrease in the formation of 4-hyroxy-tolbutamide, a tolbutamide metabolite, at the higher doses. The inhibitory effects of the investigated herbs on rat CYP2C11 was in the order: Nigella Sativa > Trigonella foenum-graecum > Ferula asafoetida. CONCLUSIONS: The 3 herbs are strong inhibitor of CYP2C11 expression, which can lead to an undesirable pharmacological effect of clinically used CYP2C11 substrate drugs with a low therapeutic index.

Potential inhibitory effect of herbal medicines on rat hepatic cytochrome P450 2D gene expression and metabolic activity.

The aim of current study was to investigate the effect of some commonly used medicinal herbs on the regulation of rat CYP2D gene expression and its metabolic activity. Wistar albino rats were treated for seven consecutive days with selected doses of five commonly used herbs (Trigonella foenum-graecum, Ferula asafoetida, Nigella sativa, Commiphora myrrha and Lepidium sativum). Thereafter, rat livers were harvested and CYP2D mRNA levels were determined by RT-PCR. The metabolic activity of CYP2D was performed on rat hepatic microsomes using dextromethorphan as specific substrate. All investigated herbs produced inhibition of CYP2D mRNA expression and metabolic activity. The inhibitory potential of investigated herbs on rat CYP2D mRNA was in the following order: Commiphora myrrha > Nigella sativa > Lepidium sativum > Trigonella foenum-graecum > Ferula asafoetida. Whereas, the inhibitory potential of investigated herbs on CYP2D mediated enzyme metabolic activity was found in following order: Nigella sativa > Lepidium sativum > Trigonella foenum-graecum > Commiphora myrrha > Ferula asafoetida. The current study shows that only used herbs reduce CYP2D activity in rat liver microsomes at the transcriptional levels. Such effects could lead to undesirable pharmacological effects of clinically used low therapeutic index CYP2D substrate drugs.

Effect of black seed on dextromethorphan O- and N-demethylation in human liver microsomes and healthy human subjects.

OBJECTIVE: To investigate the effects of black seed on the metabolic activities of CYP3A4 and CYP2D6 in human liver microsomes and in human subjects using dextromethorphan as a probe drug. METHODS: CYP2D6-mediated O-demethylation and CYP3A4-mediated N-demethylation of dextromethorphan (DEX) to dextrorphan (DOR) and 3-methoxymorphinan (3-MM), respectively, were utilized to assess the metabolic activities of the two enzymatic pathways. In the in vitro experiments, DEX was incubated with microsomes and NADPH in absence or presence of black seed extract (10-100 microg/ml) and the formation of the metabolites were measured by HPLC. In the clinical study, four healthy volunteers received a single oral dose of DEX 30 mg alone in phase I, and along with last dose of black seed (2.5 g twice daily for seven days) in phase II. Activities of the two enzymes were evaluated based on the urinary metabolic ratios (MRs), which were calculated from eight-hour urine collections. DEX and its metabolites were assayed in urine samples by HPLC following a liquid-liquid extraction. RESULTS: Black seed extracts significantly inhibited the formation of both metabolites in microsomes. The maximum inhibition was observed at the highest extract concentration (i.e., 100 microg/ml), which was about 80% and 60% for DOR and 3-MM, respectively. In the clinical study, the urinary MRs of DEX/DOR and DEX/3-MM increased by factors of 127 and 1.6-fold, respectively, after consumption of black seed. CONCLUSION: Black seed significantly inhibited CYP2D6 and CYP3A4 mediated metabolism of DEX in human liver microsomes and healthy human volunteers indicating that it has the potential to interact with CYP2D6 and CYP3A4 substrates.

Bioequivalence evaluation of 320 mg gemifloxacin tablets in healthy volunteers.

This study was done to compare the bioavailability of a new tablet formulation of gemifloxacin (gemifloxacin 320 mg/tablet) with that of the reference product (factive 320 mg/tablet). The bioequivalence of a single dose (320 mg) was assessed for gemifloxacin included in the test and reference products by comparing the pharmacokinetic parameters derived from the plasma concentration-time profiles following administration to 24 healthy male volunteers in a balanced, 2-period, 2-sequence, 2-way crossover design. Plasma concentrations of gemifloxacin were analyzed by a validated and sensitive HPLC assay developed in-house. The mean plasma concentration-time profiles are almost superimposable. 18 ANOVAs were performed to compare gemifloxacin plasma levels of the two formulations at each sampling time and there were no statistical differences between the two formulations. The parameters used to measure bioavailability were AUC0-t, AUC0-infinity and Cmax and they were calculated by a model-independent method. The parametric 90% confidence intervals of the mean values for the test/reference ratio were in each case well within the bioequivalence acceptable boundaries of 80-125% for AUCo-t, AUC0-infinity and Cmax. Data obtained in this study prove, by appropriate statistical methods, the essential similarity of plasma levels of gemifloxacin from the test product with those from the reference product suggesting equal clinical efficacy of these two products.