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Biotransformation is the major clearance mechanism of therapeutic agents from the body. Biotransformation is known not only to facilitate the elimination of drugs by changing the molecular structure to more hydrophilic, but also lead to pharmacological inactivation of therapeutic compounds. However, in some cases, the biotransformation of drugs can lead to the generation of pharmacologically active metabolites, responsible for the pharmacological actions. This review provides an update of the kinds of pharmacologically active metabolites and some of their individual pharmacological and pharmacokinetic aspects, and describes their importance as resources for drug discovery and development.

GLH8NDE, a derivative of eupatilin, is currently under development to treat dry eye disease. We conducted a randomized, double‐masked, placebo‐controlled, single‐ and multiple‐day study to evaluate safety, tolerability, pharmacodynamics, and pharmacokinetics of ocular GLH8NDE in healthy male adults. Subjects randomly received topical ocular dosing of GLH8NDE or its matching placebo for a day, then for 7 consecutive days with a 62‐h washout at one of the following daily doses: 9, 18, 36 (Koreans), and 36 mg (Whites). The study drug was administered in divided doses over 10 h with 2‐ or 5‐h intervals. Thirty‐nine (97.5%) out of 40 subjects completed the study. A total of 17 subjects experienced 31 treatment‐emergent adverse events, all of which were mild in severity and recovered without sequelae. Neither pathological changes in eye compartments nor clinically significant systemic effects were observed. GLH8NDE was rapidly absorbed reaching the peak concentration within 0.25–0.75 h postdose. The systemic exposure as measured by area under the concentration‐time curve from time of administration up to the time of the last quantifiable concentration (AUClast) after single‐day administration of the same dose was 109% higher in Koreans than in Whites. In conclusion, GLH8NDE was safe and well‐tolerated in healthy Korean and White male adults at 9–36 mg/day after single‐ and multiple‐day administrations. [ABSTRACT FROM AUTHOR]

Panax ginseng has been used as an herbal medicine for thousands of years. Most of its pharmacological effects are attributed to its constituent ginsenosides, including 20(S)-25-methoxyl-dammarane-3β, 12β, 20-triol (20(S)-25-OCH3-PPD), which is one of the protopanaxadiol type ginsenosides. It has been found to exhibit anticancer effects by interacting with multiple pharmacological pathways, such as the Wnt/β-catenin, MDM2, ERK/MAPK, and STAT3 signaling pathways. However, its therapeutic potential could be limited by its low bioavailability mainly due to its low aqueous solubility. Thus, several studies have been conducted on its pharmacokinetics and its delivery systems, so as to increase its oral bioavailability. In this review, comprehensive information on its varying pharmacological pathways in cancer, as well as its pharmacokinetic behavior and pharmaceutical strategies, is provided. This information would be useful in the understanding of its diverse mechanisms and pharmacokinetics as an anticancer drug, leading to the design of superior 20(S)-25-OCH3-PPD-containing formulations that maximize its therapeutic potential. [ABSTRACT FROM AUTHOR]

This study aimed at the evaluation of plasma level profiles of choline produced after the oral administration of choline alphoscerate ( CA). For this purpose, a high-performance liquid chromatography/tandem mass spectrometry ( HPLC/ MS/ MS) analytical method was developed and validated. Baseline correction technique was employed to monitor the CA-related choline in plasma by subtracting background levels of choline from total choline levels measured after the drug administration. Choline was well separated in the plasma matrix under the analytical conditions employed for HPLC/ MS/ MS and the analytical method developed for the monitoring of choline in plasma was well validated. The endogenous choline levels in plasma under fasting condition were measured to be 7.78 ± 1.74 µmol/L for test period 1 and 7.88 ± 1.78 µmol/L for test period 2, respectively, and were considerably increased after consumption of meals. The corrected choline levels in plasma produced only by the oral administration of CA could be evaluated by subtracting the background levels of choline monitored before the drug was administered. The pharmacokinetic parameters estimated for test and control formulations were quite similar based on the comparison of Cmax, AUC12h , and Tmax, indicating that these are biologically equivalent dosage forms. The results of our study consequently suggest that the baseline correction method in evaluating plasma concentration profiles of endogenous substances is useful. [ABSTRACT FROM AUTHOR]

Abstract: Synthesis of new ester prodrugs of olmesartan is described. Their in vitro stabilities in simulated gastric juice, rat plasma, and rat liver microsomes were tested. And the pharmacokinetic parameters for olmesartan after their oral administration were also estimated and compared with those in case of olmesartan medoxomil. Compounds 13 and 14 demonstrated high stability in simulated gastric juice and were rapidly metabolized to olmesartan in rat liver microsomes and rat plasma in vitro. In addition, C max and AUClast parameters were significantly increased in case of compounds 13 and 14 compared with olmesartan medoxomil. These results indicate that compounds 13 and 14 with cyclohexylcarboxyethyl and adamantylcarboxymethyl promoieties, respectively, are promising prodrugs of olmesartan with markedly increased oral bioavailability. [Copyright &y& Elsevier]

Abstract: Synthesis of novel amides and esters prodrugs of olmesartan is described. Their in vitro stability in rat plasma was tested. The results showed that the ester derivative IIa with n-octyl substituted dioxolone moiety was rapidly converted into olmesartan within 30min. The pharmacokinetic parameters of IIa were studied and compared with those of olmesartan medoxomil. Compound IIa is proposed to be a promising prodrug of olmesartan. [Copyright &y& Elsevier]

Abstract: The present study was aimed to investigate the effect of food components and dosing time on the oral exposure of nifedipine in rats. Nifedipine was given orally to rats with and without food components at 8:00a.m. (morning time) or 4:00p.m. (evening time) during winter periods. Food components included milk, sodium chloride, oleic acid, and sodium taurocholate. Plasma concentration profiles of nifedipine showed double peak phenomena which were generally retained regardless of food components, vehicle types and the dosing time. Sodium chloride, milk and sodium taurocholate significantly increased the AUC while oleic acid did not, when drug was dosed in the morning time. After the dosing in the evening time, milk and sodium chloride significantly increased the plasma concentrations of nifedipine but oleic acid and sodium taurocholate decreased them. Overall, the systemic in vivo exposure of nifedipine was invariably lower with the evening dosing compared to the dosing in the morning, but this circadian rhythm dependency was not reversed by the multiple dosing of food components in rats. Food components and dosing time significantly altered the oral pharmacokinetics of nifedipine in rats, implying that the altered bioavailability and higher plasma concentrations in the morning time may influence dosing regimens of nifedipine for hypertension patients. [Copyright &y& Elsevier]

Abstract: Genistein (GT) is an isoflavone from Leguminosae and has received much attention as a phytoestrogen. Genistin is a glycoside form of GT (genistein-7-O-β-d-glucopyranoside, GT-glu) is mainly found in soy-derived foods. In this study, we examined the pharmacokinetic properties and bioavailability of GT in rats and compared with those of GT-glu. In order to characterize and compare the pharmacokinetics of GT and GT-glu, these compounds were administered intravenously and orally. The plasma concentration of GT was determined by HPLC after enzymatic hydrolysis. After oral administration of GT with various doses (4, 20, 40mg/kg), the bioavailability of GT was 38.58, 24.34 and 30.75%, respectively. The T max, C max and AUC(0–∞) of GT after oral administration of GT (40mg/kg), were 2h, 4876.19ng/ml, 31,269.66ngh/ml, respectively. When smaller amount of GT was administered, the faster T max was observed. Oral administration of GT-glu resulted in longer T max, lower C max, and greater bioavailability than that of GT. The pharmacokinetic parameters of GT following oral administration of GT-glu (64mg/kg as GT-glu, 40mg/kg as GT) were obtained as follows: 8h (T max), 3763.96ng/ml (C max), 51,221.08ngh/ml (AUC(0–∞)) and 48.66% (absolute bioavailability), respectively. These results indicate that the oral bioavailability of GT-glu is greater than that of GT. [Copyright &y& Elsevier]