Volume 28, Issue 4

This review focuses on the genetic polymorphisms of the cytochrome P450 (CYP) genes in Mexican indigenous populations, who are a part of the wide ethnic diversity of this country. These native groups have a particular historical trajectory that is different from the Mexican Mestizos. This variability may be reflected in the frequency distribution of polymorphisms in the CYP genes that encode enzymes involved in the metabolism of drugs and other xenobiotics. Therefore, these polymorphisms may affect drug efficacy and safety in indigenous populations in Mexico. The present study aimed to analyze the prevalence of CYP polymorphisms in indigenous Mexicans and to compare the results with studies in Mexican Mestizos. Because the extrapolation of pharmacogenetic data from Mestizos is not applicable to the majority of indigenous groups, pharmacogenetic studies directed at indigenous populations need to be developed. The Amerindians analyzed in this study showed a low phenotypic (CYP2D6) and genotypic ( CYP2D6, CYP2C9 ) diversity, unlike Mexican Mestizos. The frequency of polymorphisms in the CYP1A1, CYP2C19, CYP2E1 , and CYP3A4 genes was more similar among the Amerindians and Mexican Mestizos, with the exception of the CYP1A2 gene, whose * 1F variant frequency in Mexican Amerindians was the highest described to date.

The cytochrome P450 2D6 (CYP2D6) belongs to a group of CYPs considered of utmost importance in the metabolism of xenobiotics. Despite being of only minor abundance in the liver, it is involved in the clearance of >25% of marketed drugs. Accordingly, CYP2D6 can be very efficiently inhibited by a couple of commonly used drugs such as some antidepressants, although induction by any drug has not been observed thus far. CYP2D6 was also one of the first enzymes for which a highly polymorphic expression could be shown leading to a widespread range of functionality, from a complete lack of a functional enzyme to overexpression due to multiplication of active alleles. A clear relationship between the CYP2D6 genotype and adverse events during treatment with CNS-active drugs such as codeine, antidepressants, or antipsychotics could be demonstrated. More recently, some new aspects emerged about the potential endogenous function of CYP2D6 in terms of behavior and brain disorders.

Background: Midazolam apparent oral clearance (CL ORAL ) is used to estimate intestinal and hepatic cytochrome P450 (CYP) 3A activity. A limited sampling approach was performed to access a midazolam partial area under the concentration time curve (AUC) to estimate CL ORAL . Methods: Midazolam plasma concentrations from healthy adults were obtained during CYP3A baseline (n=116), inhibition (n=75), and induction or activation (n=66) from seven published studies. Observed CL ORAL and partial AUCs of AUC 0-2 , AUC 0-4 , AUC 0-6 , AUC 1-2 , AUC 1-4 , AUC 2-4 , and AUC 2-6 were determined by noncompartmental analysis. Subject data were randomly divided into a training set and a validation set. Linear regression equations, derived from partial AUCs, were developed from training set data. Predicted CL ORAL was determined from these equations from validation set data. Preset criterion was a coefficient of determination ( r 2 ) greater than or equal to 0.9. Bias and precision were evaluated by relative percent mean prediction error (%MPE) and relative percent mean absolute error (%MAE). Results: During CYP3A baseline conditions, all of the evaluated CL ORAL equations had unacceptable r 2 (range: 0.34–0.86). During CYP3A inhibition, all of the evaluated CL ORAL equations had unacceptable %MAE. Acceptable r 2 , %MPE, and %MAE were observed during CYP3A induction/activation with AUC 0-4 ( r 2 =0.99, %MPE=3.9, %MAE=12.5) and AUC 1-4 ( r 2 =0.99, %MPE=6%, %MAE=11.1%). The same equations also predicted the extent of CYP3A induction as a lack of equivalence was observed with AUC 0-4 and AUC 1-4 . Conclusions: Midazolam partial AUCs were unable to estimate CYP3A activity during the evaluated baseline and inhibitory conditions. Midazolam CL ORAL utilizing a partial AUC 0-4 and AUC 1-4 was able to estimate CYP3A induction with rifampin and Ginkgo biloba extract.

Background: The use of herbs with allopathic medicines increases the possibility of herb-drug interaction, which may either be beneficial or harmful. Therefore, the present study was undertaken to determine the interaction of glibenclamide, a sulfonylurea, with the aqueous extract of garlic ( Allium sativum ), an herb used widely as an antidiabetic agent. Methods: The interaction was evaluated by an acute study, chronic study, oral glucose tolerance test, and body weight estimation in streptozotocin-induced diabetic rats. Glibenclamide was given orally at two different doses of 0.25 and 0.5 mg/kg, and A. sativum extract (ASE) was administered at the dose of 500 mg/kg. Blood glucose level and body weight estimation were carried out at various intervals. Results: The hypoglycemic effect observed with combinations of glibenclamide and ASE was greater than either of the drug given alone. Combined treatments of glibenclamide and ASE resulted in higher increase in body weight than alone treatments. Conclusions: We conclude that ASE shows a synergistic effect with glibenclamide. This could be important in reducing the dose of glibenclamide to achieve an enhanced therapeutic effect with minimal side effects.

Background: Allometric exponents in population pharmacokinetic analysis are regularly used but the issue of fixing or estimating an allometric exponent remains controversial. The objective of the current analysis is to evaluate the performance of a body-weight-dependent allometric exponent (BDE) model of remifentanil. Methods: The study was conducted in 34 patients (neonates to 17 years and 2.5 to 97 kg body weight) following a single intravenous (IV) infusion of remifentanil (5 μg/kg). A population pharmacokinetic approach was taken to describe drug clearance by the following BDE equation: CL=CL pop (BW/14.6 kg) L × BW( - M ) . Three allometric models were used to explore the impact of allometric exponents on the total clearance of remifentanil. Results: All model-fitted structural, covariate, and statistical parameters were estimated with good to excellent precision (%RSE). However, on the basis of calculated Akaike weights (0.000 for model 1, 0.004 for model 2, and 0.996 for model 3), model 3 is the most robust model to describe individual clearance estimates. Conclusions: The BDE model performed best for the estimation of remifentanil clearance and is realistic and of practical value. Further investigation should be conducted for such models.

Background: Interactions between cytochrome P450 3A4 (CYP3A4) and its substrates are complex with multiple binding sites within the active site. BI 11634 is a factor Xa inhibitor in drug development and its interaction with CYP3A4 was evaluated. Methods: Reaction phenotyping studies were conducted to determine human isoform(s) of cytochrome P450 responsible for BI 11634 metabolism using recombinant CYPs and specific chemical inhibitors. Metabolite identification and quantitation were performed for incubations of [ 14 C]BI 11634 with human liver microsomes (HLMs) or recombinant CYP3A4 (rCYP3A4) using a high-performance liquid chromatography-mass spectrometry-radiomatic detector. Inhibition of the CYP3A4-mediated metabolism of BI 11634 by quinidine was further evaluated. Results: From the reaction phenotyping studies, it was shown that the metabolism of BI 11634 in HLM was inhibited by ketoconazole and quinidine, well-accepted specific inhibitors of CYP3A4 and CYP2D6, respectively. In contrast, BI 11634 metabolism was exclusively mediated by rCYP3A4. Additional studies confirmed that BI 11634 was metabolized by CYP3A4 to form one major metabolite and this reaction was inhibited by quinidine with a K i of 7 µM. Conclusions: These data indicated that BI 11634 may interact with CYP3A4 similar to nifedipine. CYP3A4 substrates have been categorized into three subgroups, including a stand-alone subgroup for dihydropyridine calcium channel blockers such as nifedipine and felodipine. In addition, this study emphasizes the importance of using rCYP in conjunction with approaches relying on inhibition when conducting CYP450 reaction phenotyping studies, as one single method may generate misleading results. The specificity of quinidine as a CYP2D6 inhibitor is questionable as it can also significantly inhibit CYP3A4-mediated metabolism of some compounds.

Background: Some food components influence drug elimination. Previously, we found that caffeic acid, present in coffee, fruits, and vegetables, strongly inhibited human homologs of organic anion transporters (OATs) OAT1 and OAT3, which are responsible for renal tubular secretion of anionic drugs. In this study, we examined the effect of caffeic acid on drug transport by OAT1 and OAT3 in the rat kidney. Methods: The inhibitory effect of caffeic acid on rat OAT1 and OAT3 was assessed by drug uptake experiment using Xenopus laevis oocytes. Urinary excretion of phenolsulfonphthalein (PSP), a diagnostic agent secreted by renal OATs, was examined in rats, and the influence of caffeic acid was evaluated. Results: Expression of rat OAT1 (rOAT1) and rOAT3 stimulated uptake of their typical substrates, p -aminohippurate and estrone sulfate, respectively, into oocytes, and caffeic acid inhibited them dose dependently. After intravenous injection of PSP in rats, 42.7% of the dose was excreted into urine up to 60 min, and the simultaneous administration of caffeic acid reduced it to 32.0%. Conclusions: These findings show that caffeic acid inhibits OAT1 and OAT3 in the rat kidney.