Potential P-Glycoprotein-Mediated Drug-Drug Interactions of Antimalarial Agents in Caco-2 cells

Antimalarials are widely used in African and Southeast Asian countries, where they are combined with other drugs for the treatment of concurrent ailments. The potential for P-glycoprotein (P-gp)-mediated drug-drug interactions (DDIs) between antimalarials and P-gp substrates was examined using a Caco-2 cell-based model. Selected antimalarials were initially screened for their interaction with P-gp based on the inhibition of rhodamine-123 (Rho-123) transport in Caco-2 cells. Verapamil (100 mM) and quinidine (1 mM) were used as positive inhibition controls. Lumefantrine, amodiaquin, and artesunate all showed blockade of Rho-123 transport. Subsequently, the inhibitory effect of these antimalarials on the bi-directional passage of digoxin (DIG) was examined. All of the drugs decreased basal-toapical (B-A) P-gp-mediated DIG transport at concentrations of 100 mM and 1 mM. These concentrations may reflect therapeutic doses for amodiaquin and artesunate. Therefore, clinically relevant DDIs may occur between certain antimalarials and P-gp substrates in general

Pharmacokinetic Herb-Drug Interactions: Insight into Mechanisms and Consequences

Herbal medicines are currently in high demand, and their popularity is steadily increasing. Because of their perceived effectiveness, fewer side effects and relatively low cost, they are being used for the management of numerous medical conditions. However, they are capable of affecting the pharmacokinetics and pharmacodynamics of coadministered conventional drugs. These interactions are particularly of clinically relevance when metabolizing enzymes and xenobiotic transporters, which are responsible for the fate of many drugs, are induced or inhibited, sometimes resulting in unexpected outcomes. This article discusses the general use of herbal medicines in the management of several ailments, their concurrent use with conventional therapy, mechanisms underlying herb-drug interactions (HDIs) as well as the drawbacks of herbal remedy use. The authors also suggest means of surveillance and safety monitoring of herbal medicines. Contrary to popular belief that "herbal medicines are totally safe," we are of the view that they are capable of causing significant toxic effects and altered pharmaceutical outcomes when coadministered with conventional medicines. Due to the paucity of information as well as sometimes conflicting reports on HDIs, much more research in this field is needed. The authors further suggest the need to standardize and better regulate herbal medicines in order to ensure their safety and efficacy when used alone or in combination with conventional drugs

Ex Vivo and In Vivo Investigations of the Effects of Extracts of Vernonia amygdalina, Carica papaya and Tapinanthus sessilifolius on Digoxin Transport and Pharmacokinetics: Assessing the Significance on Rat Intestinal P-glycoprotein Efflux

Vernonia amygdalina (VA), Carica papaya (CP), and Tapinanthus sessilifolius (ML) are widely used in some countries as medicinal herbs to treat ailments including malaria, cancer, and diabetes. We previously reported the inhibitory effects of these herbs on permeability glycoprotein (P-gp) in Caco-2 cell monolayers. This study used ex vivo and in vivo models to investigate the likelihood of P-gp-mediated herb-drug interactions occurring. The study utilized excised rat intestinal tissues mounted in Ussing chambers to predict changes in drug absorption and an in vivo study in rats using digoxin as the P-gp substrate. Apparent permeability values and pharmacokinetic parameters of digoxin were compared to determine if co-administration of digoxin with ML, CP, or VA modulated the activity of P-gp. When VA was co-administered, the total area under the plasma concentration-time curve was significantly higher (2.1-fold) than when digoxin was administered alone. Co-administration of ML, VA, and CP significantly increased the mean digoxin apparent permeability in the mucosal-to-serosal direction by 7.8, 43.3, and 54.5%, respectively, in comparison to when digoxin was administered alone. These findings suggest that VA increases intestinal absorption of digoxin in vivo by inhibiting P-gp and may also modulate the pharmacokinetic disposition of other p-gp substrate drugs

Structural requirements for the hepatotoxicity of nonsteroidal anti-inflammatory drugs in isolated rat hepatocytes. J Pharmacol Exp Ther 287:208–213

ABSTRACT Hepatotoxicity is one of the common side effects of nonsteroidal anti-inflammatory drugs (NSAIDs). We investigated the cytotoxicity of 18 acidic NSAIDs (3 salicylic acids, 3 anthranilic acids, 6 arylacetic acids, 6 arylpropionic acids) to freshly isolated rat hepatocytes as assessed by the NSAID-induced leakage of lactate dehydrogenase (LDH) in order to determine structural requirements for the direct hepatotoxicity of the NSAIDs. Diflunisal (salicylic acids), flufenamic acid, mefenamic acid, tolfenamic acid (anthranilic acids), diclofenac, indomethacin, acemetacin (arylacetic acids) and flurbiprofen (arylpropionic acids) caused significant LDH leakage, indicating that substituent position of a carboxyl group does not relate to the hepatotoxicity of the NSAIDs. Because the cytotoxic NSAIDs were of two types as classified by their "skeleton," diphenyl and diphenylamine, we tested the cytotoxicity of the compounds. Diphenyl did not cause LDH leakage, but diflunisal, which has the diphenyl structure, was cytotoxic. On the other hand, diphenylamine induced LDH leakage to the same degree as diclofenac, which has the diphenylamine structure. Therefore, diphenylamine itself was suggested to be responsible for the cytotoxicity of diclofenac and anthranilic acids, whereas a substituted group(s) in addition to diphenyl structure seems to be important for diflunisal cytotoxicity. All of the cytotoxic NSAIDs and diphenylamine extensively decreased hepatocellular ATP content, whereas the noncytotoxic NSAID did not, indicating that the NSAID-induced decrease in ATP, probably by their uncoupling effects on mitochondrial oxidative phosphorylation, is involved in the hepatotoxicity of the NSAIDs

Population pharmacokinetic analysis of letrozole in Japanese postmenopausal women

Purpose: Letrozole is an orally active aromatase inhibitor for treatment of breast cancer. The objectives of this study were to examine pharmacokinetic profile of letrozole in Japanese subjects and identify factors which influence variability in PK of letrozole using population pharmacokinetic (PPK) analysis. Methods: Twenty-five healthy postmenopausal Japanese women were enrolled in the study and received 2.5 mg letrozole once daily for 14 or 28 days. A PPK model was developed using NONMEM software. Age, body weight (WT), AST, ALT, total bilirubin, serum creatinine (CRE), and genotype of CYP2A6 were studied as covariates. Estrone, estrone sulfate, and estradiol in plasma were measured as pharmacodynamic markers. Results: CYP2A6 genotype, CRE and AST were significant covariates for apparent systemic clearance (CL/F), and WT was a significant covariate for apparent distribution volume (Vd/F). Population mean estimates of CL/F and Vd/F in subjects without CYP2A6 mutation were 1.03 × (CRE/0.70)-1.27 × (AST/17.5)-0.793 L/hr and 94.2 × (WT/51.1)1.12 L, respectively. CL/F in subjects possessing 1 and 2 CYP2A6 mutation alleles were 84.3% and 44.8% of the value in the subjects without mutation, respectively. Estrogen levels fell to below detection limits in most subjects after letrozole administration. Three mild and transient adverse events (upper respiratory tract inflammation, arthralgia, and vomiting) were reported in the study. Conclusions: CYP2A6 genotype largely influences CL/F of letrozole. Genetic polymorphism of CYP2A6 and body weight will be causes of ethnic difference in PK. However, dose adjustment is not necessary, due to the wide therapeutic range

P-glycoprotein mediated efflux in Caco-2 cell monolayers: The influence of herbals on digoxin transport

ETHNOPHARMACOLOGICAL RELEVANCE: Several herbal medicines are concomitantly used with conventional medicines with a resultant increase in the recognition of herb-drug interactions. The phytomedicines Vernonia amygdalina Delile (VA), family Asteraceae; Azadiractha indica A. Juss (NL), family Meliaceae; Morinda lucida Benth (MLB), family Rubiaceae; Cymbopogon citratus Stapf (LG), family Poaceae; Curcuma longa L. (CUR), family Zingiberaceae; Carica papaya L. (CP), family Caricaceae and Tapinanthus sessilifolius Blume (ML), family Loranthaceae are used in African traditional medicine for the treatment of malaria. They are also used in several regions world over in managing other ailments like cancer and diabetes. This study investigated their interaction with digoxin (DIG) with a view to predict the potential of P-glycoprotein (p-gp) mediated drug-herb interactions occurring with p-gp substrate drugs. MATERIALS AND METHODS: To assess p-gp mediated transport and inhibition, bidirectional transport studies were carried out on Caco-2 cell monolayers using digoxin (DIG) as a model p-gp substrate. Cell functionality was demonstrated using the determinations of transepithelial electric resistance (TEER), cell cytotoxicity testing utilizing the MTT assay as well as the inclusion of inhibition controls. RESULTS: Under the conditions of this study, extracts of ML, VA and CP showed significant inhibition to (3)H-Digoxin basolateral-to-apical (B-A) transport at 0.02-20mg/mL; the concentrations examined. Their apical-to-basolateral (A-B) transport was further investigated. Increases in the mean A-B transport and significant decreases in the B-A transport and efflux ratio values were observed. The apparent permeability coefficient and efflux ratio were computed providing an estimate of drug absorption. CONCLUSION: The findings show that extracts of ML, VA and CP significantly inhibit p-gp in vitro and interactions with conventional p-gp substrate drugs are likely to occur on co-administration which may result in altered therapeutic outcomes