Evaluation of Nigerian Medicinal Plants Extract on Human P-glycoprotein and Cytochrome P450 Enzyme Induction: Implications for Herb-Drug Interaction

Background: Herbal medicine represents a significant component of disease prevention and therapy in most African countries. Herb-drug interactions (HDI) can arise from the co-administration of herbal and orthodox medicines. Objective: This study assessed the potential for HDI of V. amygdalina, O. gratissimum, M. oleifera, A. indica, and P. nitida extracts using in vitro assays. Little is known about these medicinal plants' potential for drug interaction despite their extensive use in Nigeria for several disease conditions. Method: The medicinal plant crude extracts were evaluated for Cytochrome P450 (CYP) enzyme induction using cryopreserved human hepatocytes. Enzyme activity was determined by quantifying probe substrate metabolism and metabolite formation using liquid chromatography-mass spectrometry/mass spectrometry. The extracts were evaluated for the potential to inhibit P-glycoprotein (P-gp) activity using human embryonic kidney membrane vesicles over-expressing human P-gp. The herbal extracts in vivo drug interaction potential was predicted based on the USFDA drug interaction guidance. Result: O. gratissimum and P. nitida methanol extracts induced CYP1A2 enzyme activity by greater than 3-fold. P. nitida methanol extracts showed over 2-fold induction of CYP1A2 mRNA expression. O. gratissimum methanol extract induced CYP2B6 mRNA expression over 2-fold. P. nitida and A. indica methanol extracts showed potent inhibition of P-gp activity (IC50: 3.8 and 5.4 µg/mL), respectively, while V. amygdalina and M. oleifera methanol extracts showed moderate P-gp inhibition (IC50: 12.1 and 37.2 µg/mL, respectively). Conclusion: Our studies suggested that the medicinal plants’ extracts can modulate CYP enzymes and P-gp activity with the potential to cause herb-drug interaction in vivo.

Evaluation of the effect of phenobarbital administration on the biochemistry profile, with a focus on serum liver values, in epileptic cats

Objectives Phenobarbital (PB) is the most common antiseizure drug (ASD) used for the management of feline epilepsy. In dogs, PB is known to cause serum liver enzyme induction and hepatotoxicity, especially after administration long term or in high concentrations. In cats, insufficient evidence is available to draw similar conclusions. The aim of this study was to evaluate the effect of PB administration on the serum biochemistry profile of epileptic cats. As an additional objective, other adverse effects arising, related to PB treatment, were recorded. Methods Medical records of four veterinary centres were retrospectively reviewed for epileptic cats receiving PB treatment. Cats were included if they had a diagnosis of idiopathic epilepsy or structural epilepsy; a normal baseline serum biochemistry profile; at least one follow-up serum biochemistry profile; no concurrent disease or had not received medication that could possibly influence liver function or lead to serum liver enzyme induction. Alkaline phosphatase, alanine aminotransferase (ALT), aspartate transaminase and gamma-glutamyl transferase activities, and total bilirubin, bile acids, glucose, albumin, total protein, urea and creatinine concentrations before and during PB administration were recorded. PB serum concentration was also recorded, when available. Results Thirty-three cats (24 males, nine females) with a median age of 3 years (range 2 months to 12 years) met the inclusion criteria. Idiopathic or structural epilepsy was diagnosed in 25 (76%) and eight (24%) cats, respectively. The follow-up period ranged from 9 to 62 months. This study found an increase in ALT in three cats, possibly related to a PB serum concentration >30 µg/ml. No statistically significant increase in serum liver enzymes or other evaluated biochemistry parameters was found by comparing pre- and post-treatment parameters. Conclusions and relevance PB administration did not result in hepatic enzyme induction or other biochemical abnormalities in cats. This strengthens the safety profile of PB as an ASD in cats.

Clinical Pharmacology and Therapeutics of Antiepileptic Drugs

This article describes clinical antiepileptic drugs (AEDs) that are available for treatment of epilepsy. Epilepsy is characterized by repeated occurrence of seizures. Epileptic seizures are classified into focal onset (partial) and generalized onset (generalized) types. Around two-dozen AEDs are available for treating epilepsy. AEDs act on diverse molecular targets to selectively modify the abnormal excitability of neurons by reducing the focal seizure discharges or preventing spread of excitation. AEDs suppress seizures by blocking the voltage-gated sodium channels (phenytoin, carbamazepine, valproate, lamotrigine, oxcarbazepine, topiramate), voltage-activated calcium channels (ethosuximide, gabapentin), potentiation of GABA inhibition (barbiturates, benzodiazepines, tiagabine), and reduction of glutamate excitation (felbamate, parampanel). Carbamazepine, phenytoin, and valproate are the first-line agents for partial onset seizures and generalized onset seizures. Ethosuximide is the drug of choice for absence seizures. AEDs are orally-active and show unique PK features. Some AEDs cause enzyme induction and hence produce drug-drug interactions. Newer AEDs such as gabapentin, levetiracetam, tiagabine, and pregabalin do not cause enzyme induction. Despite many advances in AEDs, nearly 30% of people with epilepsy have drug-resistant or intractable seizures. Presently, there is no cure for epilepsy. Thus, newer and better AEDs that can better prevent refractory seizures and modify the disease are needed for curing epilepsy.