Takeshi Hirota

Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: Consequences for pravastatin pharmacokinetics

Objective: Our objective was to quantitate the contribution of the genetic polymorphisms of the genes for 2 human organic anion transporters—organic anion transporting polypeptide C (OATP‐C) and organic anion transporter 3 (OAT3)—to the pharmacokinetics of pravastatin.

Microdosing clinical study: Pharmacokinetic, pharmacogenomic (SLCO2B1), and interaction (grapefruit juice) profiles of celiprolol following the oral microdose and therapeutic dose

The authors evaluated the contribution of the SLCO2B1 polymorphism to the pharmacokinetics of celiprolol at a microdose (MD) and therapeutic dose (TD) and compared pharmacokinetic proportionality between the 2 dose forms in 30 SLCO2B1 genotype‐matched healthy volunteers. Three drugs (celiprolol, fexofenadine, and atenolol) were orally administered as a cassette dosing following the MD (totally 97.5 μg) and then a TD (100 mg) of celiprolol, with and without grapefruit juice. The mean AUC0–24 of celiprolol was lower in SLCO2B1*3/*3 individuals (775 ng·h/mL) than in *1/*3 (1097 ng·h/mL) and *1/*1 (1547 ng·h/mL) individuals following the TD, and this was confirmed in population pharmacokinetic analysis with statistical significances; however, SLCO2B1 genotype‐dependent differences disappeared following the MD. Dose‐normalized AUC of celiprolol at the MD was much lower than that at the TD, explained by the saturation of the efflux transporter. Thus, the effect of SLCO2B1 polymorphism on the AUC of celiprolol clearly observed only at the TD may be due to the saturation of the efflux transport systems.

Population Pharmacokinetic and Pharmacodynamic Analysis of Linezolid and a Hematologic Side Effect, Thrombocytopenia, in Japanese Patients

ABSTRACT Linezolid is an antimicrobial agent to treat infections by Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). While effective, linezolid treatment frequently is associated with hematological side effects, especially thrombocytopenia. However, little is known about the mechanism of this side effect and the exposure-response relationship. The present population pharmacokinetic/pharmacodynamic (PPK/PD) study was undertaken to elucidate the factors that determine linezolid levels, the relationship between exposure to linezolid and a decrease in platelet counts, and appropriate dosage adjustments based on exposure levels. In total, 50 patients (135 plasma samples) were used for the PPK analysis. The PPK analysis revealed that renal function and severe liver cirrhosis (Child Pugh grade C) significantly affect the pharmacokinetics of linezolid according to the equation clearance (liter/h) = 2.85 × (creatinine clearance/60.9)0.618 × 0.472CIR (CIR indicates cirrhosis status; 0 for noncirrhosis, 1 for cirrhosis patients). Using 603 platelet counts from 45 patients, a PPK/PD analysis with a semimechanistic pharmacodynamic model described the relationship between linezolid exposure and platelet counts quantitatively, and the newly constructed model was validated using external data (776 platelet counts from 60 patients). Simulation indicated considerable risks in patients with insufficient renal function (creatinine clearance, ≤30 ml/min) or severe liver cirrhosis. For these patients, a reduced dosage (600 mg/day) would be recommended for sufficient efficacy (area under the concentration-time curve over 24 h in the steady state divided by the MIC, >100) and safety.

Low-temperature fabrication of polycrystalline Si thin film using Al-induced crystallization without native Al oxide at amorphous Si/Al interface

Low-temperature fabrication of polycrystalline silicon (poly-Si) thin film has been performed by Al-induced crystallization (AIC), and the structural properties have been investigated. In our experiments, to prevent native oxidation of Al film, an amorphous silicon (a-Si)/Al bilayer was formed on the SiO2/Si substrate by electron beam evaporation without breaking the vacuum. The a-Si/Al/SiO2/Si structure was then heated at a low temperature of 400°C to induce AIC. It was confirmed that layer exchange of the a-Si/Al bilayer is induced even though there is no native oxidation of Al film, which was demonstrated by scanning transmission electron microscopy and energy dispersive X-ray analysis. The mechanism for layer exchange of the a-Si/Al bilayer has been discussed. Furthermore, it was verified by scanning electron microscopy and spectroscopic ellipsometry that the a-Si/Al thickness ratio of roughly 1:1 is suitable to achieve a flat surface morphology of poly-Si. In addition, it was found, by X-ray diffraction and orientation imaging microscopy, that the Si(111)-oriented grain becomes dominant with decreasing thickness of the a-Si/Al bilayer.

Genetic polymorphisms of drug transporters: pharmacokinetic and pharmacodynamic consequences in pharmacotherapy

There has been increasing appreciation of the role of drug transporters in pharmacokinetic and pharmacodynamic consequences in pharmacotherapy. The clinical relevance of drug transporters depends on the localisation in human tissues (i.e., vectorial movement), the therapeutic index of the substrates and inherent interindividual variability. With regard to variability, polymorphisms of drug transporter genes have recently been reported to be associated with alterations in the pharmacokinetics and pharmacodynamics of clinically useful drugs. A growing number of preclinical and clinical studies have demonstrated that the application of genetic information may be useful in individualised pharmacotherapy for numerous diseases. However, the reported effects of variants in certain drug transporter genes have been inconsistent and, in some cases, conflicting among studies. Furthermore, the incidence of almost all known variants in transporter genes tends to be racially dependent. These observations suggest the necessity of considering interethnic variability before extrapolating pharmacokinetic data obtained in one ethic group to another, especially in the early phase of drug development. This review focuses on the impact of genetic variations in the function of drug transporters (ABC, organic anion and cation transporters) and the implications of these variations for pharmacotherapy from pharmacokinetic and pharmacodynamic viewpoints.

Pharmacokinetic interaction between pravastatin and olmesartan in relation to SLCO1B1 polymorphism.

AbstractThe impact of SLCO1B1 polymorphism on the pharmacokinetics of olmesartan and on the pharmacokinetic interaction between pravastatin and olmesartan was investigated. On day 1, ten healthy volunteers took an oral dose (10 mg) of pravastatin. After a 3-day washout period, each subject received olmesartan medoxomil (10 mg) for 3 days. On day 8, they received olmesartan medoxomil (10 mg) and pravastatin (10 mg) concurrently, and pharmacokinetic profiles were compared with those in each single-dose phase with regard to the SLCO1B1 genotypes (*1b/*1b, *1b/*15, and *15/*15). In the single-dose phase, the mean Cmax and AUC0-24 of olmesartan tended to be higher in *15/*15 subjects than in *1b/*1b subjects, while the mean CLt/F (±SD) in *15/*15 subjects was significantly lower than that in *1b/*1b subjects. No statistically significant differences were observed in any pharmacokinetic parameters between single-dose and co-administration phases for both pravastatin and RMS-416. These results suggest that OATP1B1 plays a role in the pharmacokinetics of olmesartan, and the co-administration of olmesartan does not affect the pharmacokinetics of pravastatin or its metabolite, RMS-416, although larger scale clinical studies are needed to confirm these observations due to the small sample size in the present study.

Epigenetic regulation of genes encoding drug-metabolizing enzymes and transporters; DNA methylation and other mechanisms

Drug metabolizing enzymes and transporters are increasingly recognized as key determinants of the inter-individual variability in pharmacokinetic (PK) and pharmacodynamic (PD) outcomes of clinically important drugs. To date, most studies investigating this variability have focused on polymorphisms (e.g. SNPs) in the genes encoding metabolic enzymes and transporters; however, it has recently been reported that the expression of some of these genes is under the control of epigenetic mechanisms. The most common epigenetic mechanism of mammalian genome regulation is DNA methylation, which does not change the genetic code but affects gene expression. Owing to its maintenance of the genomic sequence, DNA methylation is expected to offer an explanation for the controversial phenotypes of certain genetic polymorphisms. It has been recognized that DNA methylation plays a role in the transcriptional regulation of some PK/PD genes. In this review, we describe the impact of various epigenetic mechanisms, especially DNA methylation, on the expression (or activity) of drug metabolizing enzymes and transporter genes.

Drug–drug interactions that interfere with statin metabolism

Introduction: Lipid-lowering drugs, especially hydroxymethylglutaryl-CoA reductase inhibitors (statins), are widely used in the treatment and prevention of atherosclerotic diseases. The benefits of statins are well documented. However, myotoxic side effects, which can sometimes be severe, including myopathy or rhabdomyolysis, have been associated with the use of statins. In some cases, this toxicity is associated with pharmacokinetic alterations. Potent inhibitors of CYP 3A4 significantly increase plasma concentrations of the active forms of simvastatin, lovastatin and atorvastatin. Fluvastatin is metabolized by CYP2C9, while pravastatin, rosuvastatin and pitavastatin are not susceptible to inhibition by any CYP. Areas covered: This review discusses the pharmacokinetic aspects of the drug–drug interaction with statins and genetic polymorphisms in CYPs, which are involved in the metabolism of statins, and highlights the importance of establishing a system utilizing electronic medical information practically to avoid adverse drug reactions. Expert opinion: An understanding of the mechanisms underlying statin interactions will help to minimize drug interactions and develop statins that are less prone to adverse interactions. Quantitatively analyzed information for the low-density lipoprotein cholesterol lowering effects of statin based on electronic medical records may be useful for avoiding the adverse effect of statins.

Mechanisms of pharmacokinetic enhancement between ritonavir and saquinavir; micro/small dosing tests using midazolam (CYP3A4), fexofenadine (p-Glycoprotein), and pravastatin (OATP1B1) as probe drugs

We investigated the mechanisms of ritonavir‐mediated enhancement effect on the pharmacokinetics of saquinavir using in vivo probes for CYP3A4 (midazolam), p‐glycoprotein (fexofenadine), and OATP1B1 (pravastatin) following oral micro/small dosing. A cocktail of the drugs (2 mg of saquinavir, 100 µg of each probe) was administered to eight healthy volunteers (phase 1), and then coadministered with 20 mg (phase 2) and 100 mg (phase 3) of ritonavir. Plasma concentrations of the drugs were measured by validated LC–MS/MS methods. The mean plasma AUC0–24 (pg hour/mL) of saquinavir at phases 1, 2, and 3 was 101, 2 540, and 23 900 (P < .01), respectively. The relative area under the plasma concentration‐time curve (AUC)0–24 ratios of midazolam and fexofenadine at phases 1, 2, and 3 were 1:5.9:14.7 (P < .01), and 1:1.4:2.2 (P < .01–.05), respectively. In contrast, there was no difference in the pharmacokinetics of pravastatin. Inhibition of intestinal and hepatic CYP3A‐mediated metabolism, and intestinal p‐glycoprotein‐mediated efflux of saquinavir, but not OATP1B1, is involved in the enhancement mechanism. Micro/small dosing is useful for examining the mechanism of drug interactions without safety concern.

Interindividual differences in placental expression of the SLC22A2 (OCT2) gene: Relationship to epigenetic variations in the 5′-upstream regulatory region†

Organic cation transporters (OCTs) mediate the transport of organic cations and some drugs (e.g., metformin and cimetidine). OCT1, OCT2, and OCT3 are located in the imprinting cluster of the insulin-like growth factor 2 receptor. It has been reported that OCT1 and OCT3 show a biallelic expression, whereas OCT2 undergoes maternal imprinting in the human placenta; however, a loss of the imprinting of OCT2 has recently been reported in some placental samples. This study investigated whether epigenetic mechanisms are involved in interindividual differences in the placental expression of OCT2. Because OCT2 mRNA levels were higher in biallelic samples than that in monoallelic samples, we compared the DNA methylation and chromatin modifications in the promoter regions. There was no remarkable difference in DNA methylation between the mono allelic samples and biallelic samples. In contrast, histone H3 acetylation (H3Ac) was increased in the biallelic samples. A significant negative correlation was observed between the trimethylation of lysine-9 on histone H3 (H3K9me3) and the OCT2 mRNA levels. Our results suggest that H3Ac plays a role in the allelic expression of OCT2. In addition, H3K9me3 in the OCT2 promoter may explain the interindividual differences in placental OCT2 mRNA levels.