Drug Metabolism Letters - Volume 7, Issue 2, 2013

Background and Aims: Methamphetamine abuse results in numerous adverse health effects. Formation of free radicals may be a contributing factor. Methamphetamine has produced free radicals in animal studies. Present study was conducted to evaluate status of oxidative stress and lipid peroxidation among chronic methamphetamine users. Methods: Ninety six individuals were selected randomly from methamphetamine abusers who had referred to rehabilitation and treatment center for drug abuse and their closed relatives, after providing informed consent. Blood samples were taken from each of the studied individuals. Ferric reducing ability of plasma (FRAP) assay and serum level of MDA (malondialdehyde) were used to assess the total anti-oxidant power and status of lipid peroxidation of the body, respectively. The results were analyzed by SPSS software version 16.0. Differences among groups were determined by T-test. Findings: Total anti-oxidant powers of plasma were 0.31±0.04 micromoles/liter and 0.46±0.05 micromoles/liter in methamphetamine abusers and control groups respectively. The difference was statistically significant (p-value=0.04). Levels of MDA were 4.38±5.05 micromoles/liter and 1.72±2.04 micromoles/liter in methamphetamine abusers and control group. The difference was statistically significant (p-value=0.01). Conclusion: results of present study suggest that prolonged use of methamphetamine exerts oxidative stress on the body and enhances lipid peroxidation. The event may contribute to emergence of adverse effects of acute and prolonged use of methamphetamine; such as loss of attention, psychomotor dysfunction, and cognitive deficits. It is recommended that antioxidants were included in drug regimens prescribed for methamphetamine abusers who referred to physicians to seek medical care for any reason.

The purpose of this study was to evaluate the potential risk of common herbal medicines used by HIV-infected patients in Africa for herb-drug interactions (HDI). High throughput screening assays consisting of recombinant Cytochrome P450 enzymes (CYPs) and fluorescent probes, and parallel artificial membrane permeability assays (PAMPA) were used. The potential of herbal medicines to cause HDI was ranked according to FDA guidelines for reversible inhibition and categorization of time dependent inhibition was based on the normalized ratio. CYPs 1A2 and 3A4 were most inhibited by the herbal extracts. H. hemerocallidea (IC50 = 0.63 μg/mL and 58 μg/mL) and E. purpurea (IC50 = 20 μg/mL and 12 μg/mL) were the potent inhibitors of CYPs 1A2 and 3A4 respectively. L. frutescens and H. hemerocallidea showed clear time dependent inhibition on CYP3A4. Furthermore, the inhibitory effect of both H. hemerocallidea and L. frutescens before and after PAMPA were identical. The results indicate potential HDI of H. hemerocallidea, L. frutescens and E. purpurea with substrates of the affected enzymes if maximum in vivo concentration is achieved.

Alisertib (MLN8237) is an investigational potent Aurora A kinase inhibitor currently under clinical trials for hematological and nonhematological malignancies. Nonclinical investigation showed that alisertib is a highly permeable compound with high plasma protein binding, low plasma clearance, and moderate volume of distribution in rats, dogs, monkeys and chimpanzees. Consistent with the above properties, the oral bioavailability in animals was greater than 82%. The predicted human oral pharmacokinetic (PK) profile was constructed using allometric scaling of plasma clearance and volume of distribution in the terminal phase from animals. The chimpanzee PK profiles were extremely useful to model absorption rate constant, which was assumed to be similar to that in humans, based on the fact that chimpanzees are phylogenetically closest to humans. The human plasma clearance was projected to be low of 0.12 L/hr/kg, with half-life of approximately 10 hr. For human efficacious dose estimation, the tumor growth inhibition as a measure of efficacy (E) was assessed in HCT116 xenograft mice at several oral QD or BID dose levels. Additionally, subcutaneous mini-pump infusion studies were conducted to assess mitotic index in tumor samples as a pharmacodynamic (PD) marker. PK/PD/E modeling showed that for optimal efficacy and PD in the xenograft mice maintaining a plasma concentration exceeding 1 μM for at least 8-12 hr would be required. These values in conjunction with the projected human PK profile estimated the optimal oral dose of approximately 103 mg QD or 62.4 mg BID in humans. Notably, the recommended Phase 2 dose being pursued in the clinic is close to the projected BID dose.

In drug discovery and development, the kinetic study of active metabolites plays an important role, helping to define the time course of the drug in the body and its activity or toxicity. After a pharmacokinetics assessment of a drug and its metabolite or a prodrug and its parent-drug, several parameters can be calculated. In some cases, achieving the objective of the study does not require all possible parameters to be calculated. When parameters are calculated, it is essential that their denotations are widely accepted and used. However, some parameters undergo a certain variability of denotation, which may confuse some readers. Thus, this review summarizes the current published data for experimental pharmacokinetic parameters of metabolites and the calculations involved in simple metabolite pharmacokinetic studies. It also evaluates the most common pharmacokinetic parameters in the literature and suggests metabolite parameters that could be determined to help advance metabolite kinetic models.

Human hepatic organic anion-transporting polypeptides (OATPs), including OATP1B1, 1B3, and 2B1, are expressed at the basolateral membrane of hepatocytes and mediate the uptake of a variety of compounds from blood into hepatocytes. The liver-specific OATPs are increasingly recognized as playing important roles in the pharmacokinetic (PK) of many drugs and thus, involved in the clinically significant drug-drug interactions (DDIs). However, the evaluation of the specific roles of individual OATPs in hepatocytes is challenging because of the lack of selective inhibitors and probe substrates for each OATP member. In the present study, the uptake activity of OATP1B3 was examined in human hepatocytes cultured up to 14 days using an in vitro uptake assay. The results showed that OATP-mediated uptake of rosuvastatin, a substrate for OATPs declined substantially in cultured human hepatocytes. In contrast, the uptake of OATP1B3-selective substrate telmisartan was not measureable at earlier culture periods, but became detectable on Day 7 and showed culture duration-dependent changes from Day 7 to 14. Quantitative polymerase chain reaction (qPCR) analyses illustrated that the OATP functional change was not correlated with messenger ribonucleic acid (mRNA) expression alteration in hepatocytes cultured for 3 hours or 7 days. The OATP1B3-mediated telmisartan uptake was also culture medium- and donor-dependent, and only observed in 3 of 5 lots of hepatocytes cultured in 2 of 3 media tested. These results show that using human hepatocytes cultured in certain conditions may provide an excellent addition to transfected cell lines as a way to distinguish OATP1B3 from other hepatic OATP family members, such as OATP1B1, to provide more understanding of OATP-mediated clinical DDI.

Intensive Biotransformation studies on Gefitinib could play a significant role in designing and synthesizing new drugs around the core structure of Gefitinib. These studies may be useful in developing an entirely new drug by blocking the metabolic spots in Gefitinib. Gefitinib (Iressa) was the first oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. Gefitinib shows toxicity to cancer cells and has the capability to inhibit the growth of cancer cells. Gefitinib is considered as one of the selective EGFR inhibitors to be available in clinical practice. In 2003, FDA had approved Gefitinib for metastatic non-small-cell lung cancer therapy (NSCLC). However, it was observed that NSCLC Patients who responded to treatment developed resistance to Gefitinib. Hence, in the present study Gefitinib was incubated with hepatocytes to identify both phase-I and Phase-II metabolites. Identified Phase –I metabolites were due to oxidative defluorination, N-dealkylation and loss of morpholine ring. One of the phase-II metabolites identified i.e. the glutathione adduct suggests the need to modify the structure of the drug for higher potency and safety.

Pomelo fruit juice and pomelo ethylacetate extract have been shown to increase the bioavailability of some CYP3A substrates. The purpose of this study was to investigate if this effect might be contributed to by changes in CYP3A and p-glycoprotein mRNAs levels in the liver and proximal small intestine. The ethyl acetate extract of pomelo mix was administered for 7 days to 10 rabbits. Nine rabbits were administered tap water for 7 days. The administration was through oral intubation to the stomach. On the 8th day, the rabbits were sacrificed, and the liver and the proximal 15 cm of the small intestine were dissected. Total RNA was extracted from the specimens and cDNA was prepared by quantitative real-time-polymerase chain reaction (RT-PCR) using specific primers. The ethyl acetate extract of pomelo mix reduced the mRNA expression of CYP3A6 almost 5-folds in the intestine and 2-folds in the liver. In contrast, a 1-fold increase to the p-glycoprotein mRNA expression was observed under the same experimental conditions. In conclusion, the ethyl acetate extract of pomelo mix reduced the mRNA expression of CYP3A6 in both intestine and liver but to different degrees, while the p-glycoprotein mRNA expression was not reduced.