• YAKHAK HOEJI
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• v.46 no.1
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• pp.30-38
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• 2002

The elderly patients are the most frequent users of digoxin because of increased prevalence of the two primary indications for digoxin therapy, fibrillation (AE) and congestive heart failure (CHF). This study performed to observe a variation in digoxin pharamcokinetic parameters in advancing age and changing kidney function and to compare the measured clearance with the calculated clearance. The 123 drug monitoring records of inpatients who had achieved steady state concentration of digoxin at a tertiary hospital from April 1999 to October 2001 were reviewed. In advancing age, measured digoxin clearance, volume of distribution and creatinine clearance were reduced. Compared with the calculated digoxin clearance, the measured digoxin clearance was more reduced in patients without CHF Especially, in elderly patients without CHF the measured digoxin clearance was lower than the calculated digoxin clearance. In contrast to nonCHF patients the measured value was greater than the calculated value in all CHF patients. Findings from this study indicate that the calculated digoxin clearance in elderly patients without CHF substantially overestimated the true clearance. Thus, it appears that the use of calculated digoxin clearance to estimate serum digoxin concentration may result in underestimation of the true serum concentration in a number of elderly patients without CHF.

• The Korean Journal of Nuclear Medicine
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• v.21 no.1
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• pp.55-60
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• 1987

$Digoxin^{(R)}$을 복용하고 있지 않는 각27명의 만성 신부전 환자 및 신생아의 혈청에서 Gammacoat $Digoxin^{(R)}$ kit와 Amerlex Digoxin $RIA^{(R)}$ kit를 이용하여 digoxin과 교차 면역반응을 보이는 내인성 물질(이하 DLI: Digoxin-like Immunoreactivity)을 측정하여 다음의 결과를 얻었다. 1) Gammacoat $Digoxin^{(R)}$ kit로 측정시 27명의 만성 신부전 환자중 12명에서 신생아의 경우는 27명 전원에서 측정 하한치 이상의 DLI가 검출된 반면, Amerlex Digoxin $RIA^{(R)}$ kit로는 1명을 제외한 양 군의 전원에서 DLI가 관찰되지 않았다. 만성 신부전 환자에서 Gammacoat $Digoxin^{(R)}$ kit로 측정된 DLI와 혈청 BUN/Creatinine 값 사이에는 유의한 상관 관계가 없었다. 2) 만성 신부전 환자 및 신생아의 pooled sera에 가한 digoxin의 수거율은 각각 49%, 40%였다. 3) 만선 신부전 환자 및 신생아의 pooled sera에서 측정되는 DLI의 희석 curve는 정상 희석 curve와 다르다고 할 수 없었다. 4) 만성 신부전 환자의 pooled sera에서 측정되는 DLI의 16%, 그리고 신생아의 pooled sera 에서 측정되는 DLI의 20%가 trypsin에 sensitive하였다. 5) 만성 신부전 환자의 pooled sera에서 측정되는 DLI의 56%가, 그리고 신생아의 pooled sera에서 측정되는 DLI의 경우는 전체의 20%미만이 methylene chloride로 추출되었다. 이상에서 만성 신부전 환자 및 신생아의 혈청에서는 방사면역 kit의 증류에 따라 DLI가 검출되며 그 실체를 알기 위해서는 더욱 연구가 필요하다고 할 수 있었다.

• Microbiology and Biotechnology Letters
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• v.22 no.6
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• pp.651-658
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• 1994

For the production of digoxin by using biotransformation in suspension-cultured Digita- lis lanata cells, a two-stage culture process was optimized. Modified Murashige and Skoog medium was used for growth in the first stage and the cells were transferred to glucose solution for the production of digoxin from digitoxin via biotransformation in the second stage. When the cells were cultivated for 10 days in the growth period, 12$\beta$-hydroxylation capacity was the best. It was found that the optimum amount of digitoxin as substrate was 400 mg/l with initial cell density of 21%. Maximum productivity was achieved 5 days after transfer of cells to production medium. Sucrose and fructose provided similar digoxin yield as that in glucose, and 6% was proved to be the best glucose solution. Most of the components of modified MS medium except phosphate reduced the efficiency of digoxin formation. Besides, peptone and beef extracts inhibited 12$\beta$-hydroxylation, while promoting glucosylation. Finally, it was apparent that light enhanced the formation of digoxin significantly.

• Archives of Pharmacal Research
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• v.26 no.9
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• pp.768-772
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• 2003

Tween 80 (Polysorbate 80) is a hydrophilic nonionic surfactant commonly used as an ingredient in dosing vehicles for pre-clinical in vivo studies (e.g., pharmacokinetic studies, etc.). Tween 80 increased apical to basolateral permeability of digoxin in Caco-2 cells suggesting that Tween 80 is an in vitro inhibitor of P-gp. The overall objective of the present study was to investigate whether an inhibition of P-gp by Tween 80 can potentially influence in vivo absorption of P-gp substrates by evaluating the effect of Tween 80 on the disposition of digoxin (a model P-gp substrate with minimum metabolism) after oral administration in rats. Rats were dosed orally with digoxin (0.2 mg/kg) formulated in ethanol (40％, v/v) and saline mixture with and without Tween 80 (1 or 10％, v/v). Digoxin oral AUC increased 30 and 61％ when dosed in 1 ％ and 10％ Tween 80, respectively, compared to control (P＜0.05). To further examine whether the increase in digoxin AUC after oral administration of Tween 80 is due, in part, to a systemic inhibition of digoxin excretion in addition to an inhibition of P-gp in the GI tract, a separate group of rats received digoxin intravenously (0.2 mg/kg) and Tween 80 (10％ v/v) orally. No significant changes in digoxin IV AUC was noted when Tween 80 was administered orally. In conclusion, Tween 80 significantly increased digoxin AUC and Cmax after oral administration, and the increased AUC is likely to be due to an inhibition of P-gp in the gut (i.e., improved absorption). Therefore, Tween 80 is likely to improve systemic exposure of P-gp substrates after oral administration. Comparing AUC after oral administration with and without Tween 80 may be a viable strategy in evaluating whether oral absorption of P-gp substrates is potentially limited by P-gp in the gut.

• YAKHAK HOEJI
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• v.58 no.1
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• pp.40-46
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• 2014

Drugs with a narrow therapeutic index (NTI) require very precise dosing. Warfarin and digoxin are the examples of NTI-drugs and dosing of them varies widely for different patients. However, in South Korea, only two strengths of warfarin and one of digoxin are commercially available. This is a big barrier for the precise dispensing and has potential safety risks to patients, particularly to elderly patients. To find a potential solution to the problem, an analysis of the prescribed doses and dispensing patterns of those drugs was performed. Data were collected by computer-facilitated prescription review in a university hospital. The period screened was from May 1st, 2012 to April 30th, 2013. All the prescriptions with either warfarin or digoxin tablets were selected for this study and dispensing patterns were analyzed according to the prescribed doses. A total of 17,017 warfarin prescriptions were analyzed; 8,148 for inpatient prescriptions, 8,869 for outpatient prescriptions, respectively. Of the 23 kinds of prescribed doses, 2 mg (19.9%) was most frequent, followed by 3 mg (13.2%) and 2.5 mg (11.7%). By analyzing the dispensing patterns, 60.3% (10,253) of the prescriptions required pill splitting and 72.0% of them were for the patients 65 years old and over. On the other hand, 4,350 digoxin prescriptions were included in this study. Of the 6 kinds of prescribed doses, 0.125 mg (71.2%) was most frequent, followed by 0.0625 mg (20.2%). Among the prescriptions for digoxin, 92.0% (3,998) should be split and 65.7% of them were for the patients aged 65 years and over. Despite limitations of strengths, various doses of warfarin and digoxin were prescribed. Furthermore, more than half of the prescriptions that required pill splitting were for elderly patients. The results from this study suggest that different strengths of warfarin and digoxin should be provided for accuracy of dispensing and safety for patients receiving them.

• Bulletin of the Korean Chemical Society
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• v.24 no.1
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• pp.70-74
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• 2003

The heterogeneous bioluminescence immunoassay for digoxin was developed using photoprotein, native aequorin as a label and the site-directed immobilization technique based on avidin/biotin interaction. Aequorin is a bioluminescence protein, originally isolated from the jellyfish Aequoria Victoria and an attractive label in analytical applications because of sensitive detection due to virtually no background bioluminescent signal. Digoxin is a cardioactive drug, and its therapeutic level in serum is at low concentration with very narrow therapeutic index. The aequorin-digoxigenin conjugates were synthesized by the N-hydroxysuccinimide ester method and characterized in terms of bioluminescent residual activity. The resulting dose-response curve shows that the detection limit is $1.0\;{\times}\;10^{-10}\;M$ and a dynamic range is three orders of magnitude, which was obtained by $1.0\;{times}\;10^{-10}\;M$ conjugate and 0.9 μg/mL anti-digoxin antibody. Three structurally similar molecules to digoxin were examined for their cross-reactivity. None of these three compounds showed any crossreactivity with digoxin antibody employed in this study. Standard amounts of digoxin corresponding to the therapeutic range were spiked into the each serum solution. Study of the serum matrix effect indicated that correlation coefficient shows good agreement between luminescence light intensity between in buffer and in serum.

• Biotechnology and Bioprocess Engineering:BBE
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• v.4 no.1
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• pp.32-35
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• 1999

Addition of ${\beta}$-cyclodextrin (${\beta}$-CD) polymer during the biotransformation of digitoxin into digoxin using cell suspension cultures of Digitalis lanata enhanced the conversion yield. Digitoxin showed better adsorption to CD polymer compared to digoxin, so that the optimization of addition time was found to be necessary. In the case of adding CD polymer 24 hours after the feeding of substrate digitoxin, the highest digoxin production could be achieved. At this period, digitoxin was almost consumed by cells and productivity was proportionally enhanced according as the amount of substrate was increased. Immobilization of CD polymer did not promote the biotransformation. When 3.33 g/L of CD selective inclusion complex formation could be expected. Adsorption rate was found to be rapid and saturation was obtained within 10 hours of contact.

• Journal of Microbiology and Biotechnology
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• v.8 no.5
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• pp.478-483
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• 1998

For the enhanced production of a cardiac glycoside, digoxin, using in situ adsorption by biotransformation from digitoxin in plant cell suspension cultures, selection of proper resins was attempted and the culture conditions were optimized. Among various kinds of resins tested, Amberlite XAD-8 was found to be the best for digoxin production in considering adsorption characteristics as well as the effect on cell growth. Adequate time for resin addition was determined to be 36 h from the beginning of biotransformation and the presence of resins should be as short as possible to increase the productivity. In addition, to prevent the cells from direct contact with resin particles, immobilized systems were designed and examined. Immobilization further improved the advantages of in situ adsorption. It was confirmed that the increase of the contact area for mass transfer was an important factor in utilizing an immobilized system to enhance digoxin production.

• Proceedings of the Botanical Society of Korea Conference
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• 1995.06a
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• pp.79-90
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• 1995

Production of a cardiac glycoside, digoxin, by 12$\beta$-hydroxylation from digitoxin was studied in plant cell suspension cultures of Digitalis lanata. In order to increase the conversion yield, various culture conditions including immobilization were investigated and optimized. Since digoxin was released in the medium temporarily and converted further into a glucosylated product, deacetyllanatoside C, in situ adsorption of digoxin was employed to recover the product continuously. Amberlite resin XAD-8 showed the best adsorption characteristics for digoxin among the examined resins, and an integrated process was developed to increase the productivity. In addition, it was found that the utilization of $\beta$-cyclodextrin to entrap digoxin during the culture enhanced the biotransformation yield significantly.

• Archives of Pharmacal Research
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• v.17 no.2
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• pp.80-86
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• 1994

The bioavailability of digoxin generic tablets manufactures in Korea (formulations A & B) wwere compared to a standard (formulation C; Lanoxin brand digoxin, Burroughs Wellcome, USA) in 12 healthy Korean male volunteers (mean age 31.4 years) in a single dose, randomized, complete block crossover study. Using a latin square design, each of the subjects was randomized to the order number and allocated to each of the three treatments of 0.5mg oral digoxin. Digoxin conc4ntrations in serum and urine samples collected for 48 hours after dosing were measured by fluoprescence polarization immunoassy and radioimmunoassy, respectively. Treatments were compared by using nonlinear least squares regession analysis to evaluate the following pharmacokinetic parameters : maximum serum concentation $(C_{max})$; time of maximum serum concentation $(T_{max})$; area under the serum concentration-time curve $AUC_{0-12}$, $C_{max}$\;and\;(AUC_{0-12})$; and cummulative urinary excretion for 0-48 hours $(CLE_{0-48}.\;Mean\;AUC_{0-12},\;C_{max},\;and\;CUE_{0-48}$ values for formulations B and C were significantly different from formulation A (P<0.001), but not significantly diffeerent form each other. Basede on $AUL_{0-12}\;and\;CUE_{0-48}$ respectively, the relative availability of formulation B was 87.5% and 89.6% and the relative availability of formultation A was 43% and 35% when compared to formulation C(the standard).