Influence of the <i>CYP3A5</i> and <i>MDR1</i> genetic polymorphisms on the pharmacokinetics of tacrolimus in healthy Korean subjects

Choi, Ji H.,Lee, Yoon J.,Jang, Seong B.,Lee, Jong-Eun,Kim, Kyung H.,Park, Kyungsoo Blackwell Publishing Ltd 2007 British journal of clinical pharmacology Vol.64 No.2

<P><B>What is already known about this subject</B></P><P>• It was found that the genetic polymorphisms of <I>CYP3A5, CYP3A4</I> and <I>MDR1</I> could affect the pharmacokinetics of tacrolimus.</P><P>• This study was conducted to find such a possibility in the Korean population.</P><P><B>What this study adds</B></P><P>• <I>CYP3A5</I> polymorphisms are likely to be associated with altered pharmacokinetics of tacrolimus in Koreans.</P><P>• <I>MDR1</I> polymorphisms have no important role in the pharmacokinetics of tacrolimus.</P><P>Aims</P><P>To determine the frequencies of the genotypes of <I>CYP3A5</I> and <I>MDR1</I> and to examine the influence of the polymorphisms of these genes on tacrolimus pharmacokinetics in the Korean population.</P><P>Methods</P><P>Twenty-nine healthy Koreans who participated in the previous tacrolimus pharmacokinetic study were genotyped for <I>CYP3A4</I>*<I>1B</I>, <I>CYP3A5</I>*<I>3</I>, <I>MDR1</I> c.1236C→T, <I>MDR1</I> c.2677G→A/T and <I>MDR1</I> c.3435C→T. The relationship between the genotypes so obtained and tacrolimus pharmacokinetics observed in the previous study was examined.</P><P>Results</P><P>No subject in this study had the <I>CYP3A4</I>*<I>1B</I> variant. The observed frequencies of <I>CYP3A5</I>*<I>1/</I>*<I>1</I>, *<I>1/</I>*<I>3</I>, and *<I>3/</I>*<I>3</I> were 0.069 [confidence interval (CI) −0.023, 0.161], 0.483 (CI 0.301, 0.665) and 0.448 (CI 0.267, 0.629), respectively. AUC<SUB>0–∞</SUB> for the <I>CYP3A5</I>*<I>1/</I>*<I>1</I> or *<I>1/</I>*<I>3</I> genotype was 131.5 ± 44.8 ng h ml<SUP>−1</SUP> (CI 109.6, 153.5), which was much lower compared with the <I>CYP3A5</I>*<I>3/</I>*<I>3</I> genotype of 323.8 ± 129.3 ng h ml<SUP>−1</SUP> (CI 253.5, 394.1) (<I>P </I>= 2.063E−07). Similarly, <I>C</I><SUB>max</SUB> for the <I>CYP3A5</I>*<I>1/</I>*<I>1</I> or *<I>1/</I>*<I>3</I> genotype was 11.8 ± 3.4 ng ml<SUP>−1</SUP> (CI 10.1, 13.5), which was also much lower compared with the <I>CYP3A5</I>*<I>3/</I>*<I>3</I> genotype of 24.4 ± 12.3 ng ml<SUP>−1</SUP> (CI 17.8, 31.1) (<I>P </I>= 0.0001). However, there was no significant difference in tacrolimus pharmacokinetics among the <I>MDR1</I> diplotypes of CGC-CGC, CGC-TTT, CGC-TGC, TTT-TGC or TTT-TTT (<I>P </I>= 0.2486).</P><P>Conclusions</P><P>This study shows that the <I>CYP3A5</I>*<I>3</I> genetic polymorphisms may be associated with the individual difference in tacrolimus pharmacokinetics. An individualized dosage regimen design incorporating such genetic information would help increase clinical efficacy of the drug while reducing adverse drug reactions.</P>

Pharmacokinetics of amikacin in plasma of healthy goats after intravenous injection once daily for three days

Naseem, Sania,Sultana, Mudasir,Raina, Rajinder,Pankaj, Nrip Kishore,Verma, Pawan Kumar,Nasir, Nasir Ahmad,Ahanger, Azad Ahmad,Rahman, Shafiqur,Prawez, Shahid The Korean Society of Veterinary Science 2011 大韓獸醫學會誌 Vol.51 No.4

Amikacin is a semisynthetic derivative of kanamycin and primarily active against aerobic Gram-negative-pathogens with limited activity against Gram-positive bacteria. Meager study was reported on pharmacokinetic data on multi-days administration of amikacin. Hence, pharmacokinetics study was done in five clinically healthy goats (n = 5), after intravenous bolus injection of amikacin sulfate at the dose rate of 10 mg/kg body weight daily for three consecutive days. The amikacin concentrations in plasma and pharmacokinetics-parameters were analyzed by using microbiological assay technique and noncompartmental open-model, respectively. The mean peak plasma concentrations (Mean ${\pm}$ SD) of amikacin at time zero ($Cp^{0}$) was $114.19{\pm}20.78$ and $128.67{\pm}14.37{\mu}g/mL$, on day 1st and 3rd, respectively. The mean elimination half-life ($t_{1/2}ke$) was $1.00{\pm}0.28h$ on day 1st and $1.22{\pm}0.29h$ on day 3rd. Mean of area under concentration-time curve ($AUC_{0{\rightarrow}{\infty}}$) was $158.26{\pm}60.10$ and $159.70{\pm}22.74{\mu}g.h/mL$, on day 1st and 3rd respectively. The total body clearance ($Cl_{B}$) and volume of distribution at steady state (Vdss) on day 1st and 3rd were $Cl_{B}=0.07{\pm}0.02$ and $0.06{\pm}0.01L/h.kg$ and $Vdss=0.10{\pm}0.03$ and $0.11{\pm}0.05L/kg$, respectively. No-significant difference was noted in both drug-plasma concentration and pharmacokinetics-parameters, respectively. Amikacin concentration in plasma was found higher up-to 4 h and 6 h onward on down-ward trends favour to reduce toxicity. Which also support the pharmacokinetic-pharmacodynamic way of dosing of aminoglycosides and hence, amikacin may be administered 10 mg/kg intravenously daily to treat principally Gram-negative pathogens and limitedly Gram-positive-pathogens.

A Detailed Analysis of Alcohol Pharmacokinetics in Healthy Korean Men

조성엽,한혜경,신광희,안형미,유경상,송병준,유성호 대한법의학회 2015 대한법의학회지 Vol.39 No.2

To determine blood alcohol concentration (BAC) by extrapolation, an understanding of basal pharmacokinetics is indispensable. Breath alcohol concentration (BrAC) has been used for the determination of body alcohol concentration replaced by BAC in Korea. Therefore, the determination of BAC/BrAC ratio is a key problem in alcohol pharmacokinetics. Among several factors, the ingested dose of alcohol and the allelic variation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) are the most significant factors influencing the pharmacokinetic parameters, particularly in the absorption and elimination phases. This study shows a detailed pharmacokinetic analysis of BAC and BrAC associated with genetic polymorphism including ALDH2 in 42 healthy Korean men. The change in the alcohol dose ingested influenced the maximum concentration (Cmax), the time to reach Cmax (Tmax), the absorption rate constant (K01), the area under the concentration-time curve (AUClast), and the hourly elimination rate. The conversion of wild-type 487Glu (ALDH2*1) to 487Lys (ALDH2*2) in human ALDH2 resulted in changes in Cmax (ALDH2*1/*1, 0.03±0.01 g/dL [±standard deviation] vs. ALDH2*1/*2, 0.05±0.004 g/dL [P<0.01]), AUClast (ALDH2*1/*1, 4.48±2.19 g∙min/dL vs. ALDH2*1/*2, 7.52±1.26 g∙min/dL [P<0.05]), and the BAC elimination rate (ALDH2*1/*1, 0.05±0.02 g/L/hr vs. ALDH2*1/*2, 0.09±0.01 g/L/hr [P<0.05]). Moreover, the comparison of BAC and BrAC by Bland-Altman plot showed good agreement, suggesting that the measurement of BrAC can be a good alternative for the determination of BAC, particularly in the post-absorption phase. These results provide fundamental information about the pharmacokinetics of alcohol and the determination of BAC in forensics.

Effects of Acute Moderate Hypoxemia on Kinetics of Metoclopramide and its Metabolites in Chronically Instrumented Sheep

JohnKim,K.WayneRiggs,DanW.Rurak 대한약학회 2002 Archives of Pharmacal Research Vol.25 No.5

Hypoxemia is known to induce various physiological changes which can result in alteration in drug pharmacokinetics. To examine the effect of acute moderate hypoxemia on metoclopramide (MCP) pharmacokinetics, a continuous 14-hour infusion of MCP during a normoxemic, hypoxemic and subsequent normoxemic period was conducted in eight adult sheep. Arterial blood and urine samples were collected to examine the effects on the pharmacokinetics of MCP and its deethylated metabolites. MCP and its mono- and di-deethylated metabolites were quantitated using a GC/MS method. Steady-state concentrations of MCP were achieved in each of the three periods. During hypoxemia, MCP plasma steady-state concentration increased significantly from 50.72 ± 1.06 to 63.62 ± 1.79 ng/mL, and later decreased to 55.83 ± 1.15 ng/mL during the post-hypoxemic recovery period. Total body clearance (CLTB) of MCP was significantly decreased from 274.2 ± 48.0 L/h to 205.40 ± 28.2 L/h during hypoxemia, and later restored to 245.8 ± 44.2 L/h during the post-hypoxemic period. Plasma mono-deethylated MCP concentration (32.78 ± 1.73 ng/mL) also increased, compared to the control group (21.20 ± 1.39 ng/mL), during hypoxemia and subsequent normoxemic period. Renal excretion of MCP and its metabolites was also decreased during hypoxemia, while urine flow was increased with a concomitant decrease in urine osmolality. Thus, the results indicate that acute moderate hypoxemia affects MCP pharmacokinetics.

A mechanism-based understanding of altered drug pharmacokinetics by gut microbiota

Gulnaz Aneela,Chang Ji-Eun,맹한주,Shin Kwang-Hee,Lee Kyeong-Ryoon,Chae Yoon-Jee 한국약제학회 2023 Journal of Pharmaceutical Investigation Vol.53 No.1

Background Pharmacomicrobiomics, which has recently emerged as a new strategy for personalized medicine, is the investigation of the influence of microbial variability on drug pharmacokinetics, efficacy, and safety. The roles of gut microbiota in drug pharmacokinetics should be thoroughly investigated, given the significant implications of gut microbiota in humans. Area covered In this paper, we provide a mechanism-based review of the impact of the gut microbiota on drug pharmacokinetics, primarily based on drug metabolism and transporters. The main mechanisms presented here are the direct metabolism of drugs by gut microbiota activity, modulation of relevant gene expression, and competitive inhibition using their metabolites. We also present the limitations of current research and provide perspectives for future investigations. Expert opinion Although prominent advances in research have paved the way to link gut microbiota and drug pharmacokinetics, there are still some limitations and restrictions to understand their intricate association. Particular attention should be paid to studies using germ-free or antibiotic-treated animals to determine associations between gut microbiota and drug pharmacokinetics. Technical limitations may also hamper advances in research on microbiota, and the expanded use of -omics techniques is expected to further improve the accuracy and efficiency of microbial investigations. More translational research that links clinical and in vitro/pre-clinical studies is warranted to facilitate microbiome-based personalized therapy.

Effects of CYP2C19 genetic polymorphism on the pharmacokinetics of tolperisone in healthy subjects

Chang-Keun Cho,Ji-Young Byeon,Pureum Kang,Hye-Jung Park,Eunvin Ko,Chou Yen Mu,Choon-Gon Jang,Seok-Yong Lee,Yun Jeong Lee 대한약학회 2023 Archives of Pharmacal Research Vol.46 No.2

Tolperisone hydrochloride is a centrally-acting muscle relaxant used for relieving spasticities of neurological origin and muscle spasms associated with painful locomotor diseases. It is metabolized to the inactive metabolite mainly by CYP2D6 and, to a lesser extent, by CYP2C19 and CYP1A2. In our previous study, the pharmacokinetics of tolperisone was significantly affected by the genetic polymorphism of CYP2D6, but the wide interindividual variation of tolperisone pharmacokinetics was not explained by genetic polymorphism of CYP2D6 alone. Thus, we studied the effects of CYP2C19 genetic polymorphism on tolperisone pharmacokinetics. Eighty-one subjects with different CYP2C19 genotypes received a single oral dose of 150 mg tolperisone with 240 mL of water, and blood samples were collected up to 12 h after dosing. The plasma concentration of tolperisone was measured by a liquid chromatography-tandem mass spectrometry system. The CYP2C19PM group had significantly higher Cmax and lower CL/F values than the CYP2C19EM and CYP2C19IM groups. The AUCinf of the CYP2C19PM group was 2.86-fold and 3.00-fold higher than the CYP2C19EM and CYP2C19IM groups, respectively. In conclusion, the genetic polymorphism of CYP2C19 significantly affected tolperisone pharmacokinetics.

Pharmacokinetics, pharmacodynamics, and tolerability of LC350189, a novel xanthine oxidase inhibitor, in healthy subjects

Yoon, Seonghae,Shin, Donghoon,Lee, Howard,Jang, In-Jin,Yu, Kyung-Sang Dove Medical Press 2015 Drug design, development and therapy Vol.9 No.-

<P><B>Introduction</B></P><P>LC350189 is a novel selective xanthine oxidase inhibitor under clinical development for the management of hyperuricemia in gout patients. The aim of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of the drug in healthy subjects.</P><P><B>Methods</B></P><P>A dose-block randomized, double-blind, active and placebo-controlled, single- and multiple-dosing study was conducted. A single ascending dose (SAD) study (10–600 mg) and a multiple ascending dose (MAD) study with once-daily doses (100–800 mg) for 7 days were conducted. Serial samples of blood and urine for pharmacokinetics/pharmacodynamics analysis were collected, and tolerability and adverse events were assessed throughout the study.</P><P><B>Results</B></P><P>Sixty-seven and 58 subjects were enrolled in the SAD and MAD studies, respectively. The mean <I>C</I><SUB>max</SUB> and AUC<SUB>last</SUB> values increased with increasing doses, and exposure to LC350189 was dose proportional. The 24-hour mean serum uric acid (<I>C</I><SUB>mean,24</SUB>) decreased by 8.7%–31.7% (day 1) and 53.5%–91.2% (day 7) from baseline in the SAD and MAD studies, respectively, and the percentage decrease in <I>C</I><SUB>mean,24</SUB> increased with higher doses.</P><P><B>Conclusion</B></P><P>LC350189 was well tolerated in the dose range of 10–800 mg. It lowered the serum and urine uric acid levels substantially in this dose range; the extent of the decrease in the serum uric acid level in the 200 mg dose group was similar or higher compared to that of febuxostat 80 mg group in the MAD study. It is expected that LC350189 could be safely administered once daily to patients with hyperuricemia or gout, leading to a sufficient decrease in uric acid levels.</P>

Haloperidol의 약물속도론적 연구 (III) -정신분열증 환자에 있어서 Haloperidol의 일회 주사 및 경구투여시의 Pharmacokinetics-

박경호(Kyoung Ho Park),이민화(Min Hwa Lee),이명걸(Myung Gull Lee),권준수(Jun Soo Kwon),박원명(Won Myung Park),박진생(Jin Seng Park) 대한약학회 1990 약학회지 Vol.34 No.6

The pharmacokinetics of haloperidol were determined after single oral and intravenous doses in 13 male schizophrenic patients. Plasma concentrations of haloperidol(HP) and reduced haloperidol were measured by high performance liquid chromatography. Plasma concentration data obtained were analyzed by obth model dependent (one-or two exponential decay models using nonlinear regression) and model independent (AUC and first moment curve) approaches. The two methods were found to be in close results. After intravenous injections of HP in 8 patients (10 mg/man), the mean central and peripheral volume of distribution were 2.85+/-1.7O and 8.09+/-2.10 l/kg, respectively, and mean steady, state volume of distribution was 11.87+/-3.21 l/kg. Mean clearance, MRT and elimination half life were 12.39+/-3.25 ml/min/kg, 925.1O+/-166.79 min and 676.35+/-126.45 min,respectively. After oral administrations of HP in 5 patients, mean peak time and peak concentration were 2l7.63+/-61.60min and 9.77+/-2.92ng/ml, respectively. Mean MRT and elimination half life were 1112.23+/-131.73 min and 724.02+/-120.03 min, respectively, and these parameters were not significantly different from those of intravenous injection of HP. Absolute bioavailability of HP oral product was found to be about 44%. The profiles of plasma RH concentration-time curves after oral or intravenous doses of HP were similar. Also it was found that the elimination rate of RH was slower than that of HP by comparing the slopes of plasma concentration-time curves of HP and RH.

Effects of Water Deprivation on Drug Pharmacokinetics: Correlation between Drug Metabolism and Hepatic CYP Isozymes

Lee, Joo-Hyun,Oh, Jung-Mi,Lee, Myung-Gull 대한약학회 2008 Archives of Pharmacal Research Vol.31 No.8

Male Sprague-Dawley rats deprived of water for 72 h (a rat model of dehydration) showed no change in protein expression of the hepatic microsomal cytochrome P450 (CYP) 1A2, 2B1/2, 2C11, or 3A1/2, but an increase in protein expression (3-fold) and mRNA level (2.6-fold) of CYP2E1. Glucose feeding instead of food normalized CYP2E1 protein expression during dehydration. Here, we review how dehydration can change the pharmacokinetics of drugs reported in the literature via changing CYP isozyme levels. We also discuss how dehydration changes the pharmacokinetics of drugs that are metabolized via renal DHP-I, or are mainly excreted in the urine and bile, and form conjugates.

Evaluation of the pharmacokinetics and metabolism of a novel histone deacetylase inhibitor, KBH-A40, in rats

Oh, S. J.,Lee, K.,Ryu, J.,Yu, H. E.,Han, G.,Park, S. K.,Kang, J. S.,Kim, H. M.,Kim, Y. C. Informa Healthcare 2011 Xenobiotica Vol.41 No.2

<OL><LI><P>The pharmacokinetics and metabolism of KBH-A40, a novel <I>δ</I>-lactam-based histone deacetylase inhibitor, were characterized in male Sprague-Dawley rats. KBH-A40 exhibited a high clearance (12.0 ± 2.8 l h<SUP>−1</SUP>kg<SUP>−1</SUP>), a large volume of distribution at steady state, <I>V</I><SUB>ss</SUB> (3.9 ± 1.5 l kg<SUP>−1</SUP>), and a short half-life, <I>t</I><SUB>1/2</SUB> (2.0 ± 0.3 h).</P></LI><LI><P>KBH-A40 was rapidly converted to its metabolite, KBH-A40 carboxylate, after intravenous (2 and 20 mg kg<SUP>−1</SUP>) and oral (10 mg kg<SUP>−1</SUP>) administration; the carboxylate metabolite remained at elevated concentrations in the plasma for more than 8 h. Glucuronide conjugate of KBH-A40 was identified qualitatively by using liquid chromatography tandem mass spectrometry in rat plasma.</P></LI><LI><P>KBH-A40 was rapidly absorbed (<I>t</I><SUB>max</SUB> = 0.4 h) after oral dose, consistent with its permeability in Caco-2 cells. Its oral bioavailability was low (14.2-14.8%). An apparent “double peak” phenomenon was observed for both KBH-A40 and KBH-A40 carboxylate after oral administration.</P></LI><LI><P>KBH-A40 was degraded rapidly by glucuronidation, but not by cytochrome P450-mediated oxidation, in rat liver microsomes.</P></LI><LI><P>These results suggest that the rapid metabolism of KBH-A40 could be a major reason for its poor pharmacokinetics. Therefore, this work provides valuable structural information to improve pharmacokinetic properties of KBH-A40, a lead compound.</P></LI></OL>