Ronald C. Li

Triterpene antioxidants from Ganoderma lucidum

Ganoderma lucidum was studied for its antioxidative activity by bioassay guided isolation in conjunction with in vitro tests. The powdered crude drug was treated with boiling water and the aqueous extract (Ex1) was further separated to obtain terpene and polysaccharide fractions. The two fractions and Ex1 were screened for their antioxidative effect against pyrogallol induced erythrocyte membrane oxidation and Fe (II)‐ascorbic acid induced lipid peroxidation. All tested samples showed antioxidative activities in a dose dependent manner and the terpene fraction was found to possess the highest effect compared with the others. Chemical isolation of the terpene fraction resulted in the detection of ganoderic acids A, B, C and D, lucidenic acid B and ganodermanontriol as major ingredients. Copyright

Possible influences of ginseng on the pharmacokinetics and pharmacodynamics of warfarin in rats

We evaluated the significance of a reported clinical case of drug‐drug interaction between ginseng and warfarin using a robust pharmacokinetic/pharmacodynamic approach in a rat model.

Achieving an Optimal Outcome in the Treatment of Infections The Role of Clinical Pharmacokinetics and Pharmacodynamics of Antimicrobials

Over the past few decades, the importance of applying pharmacokinetic principles to the design of drug regimens has been increasingly recognised by clinicians. From the perspective of antimicrobial chemotherapy, an improvement in clinical outcome and/or a reduction in toxicity are of primary interest. Before application of these pharmacokinetic theories can be effective, the interrelationships between antimicrobial, pathogen and host factors must be clearly defined. Information regarding the pharmacokinetics of the antimicrobial and the quantification of pathogen susceptibility is required.Even though susceptibility end-points such as minimum inhibitory concentration (MIC) and minimum bactericidal concentration are widely employed, they do not provide any information on dynamic changes of bacterial densities. In this regard, time-kill studies can provide more basic knowledge of the complex bacterial responses to the antimicrobial. Better prediction of these responses can be afforded by the use of mathematical models.More recently, various surrogate end-points employing a combination of suitable pharmacokinetic parameters and susceptibility data, for example the ratio of peak concentration to MIC, the area under the concentration-time curve above the MIC (AUC>mic), the time above the MIC, or the area under the inhibitory curve (AUIC), have been suggested for better prediction of the activity of different classes of antimicrobials. To allow more extensive investigations of the contribution of pharmacokinetics to the pharmacodynamics of antimicrobials, various in vitro kinetic models have been developed. However, certain limitations exist, and it is necessary to avoid over-interpretation of the data generated by these models. Two important microbial dynamic responses, postantibiotic effect and resistance selection, must be further explored before the full impact of pharmacokinetics on antimicrobial chemotherapy can be depicted.The present paper aims at discussing all the relevant factors and provides some pertinent information on the use of pharmacokinetic-pharmacodynamic principles in antimicrobial therapy.

Efficient high-performance liquid chromatographic assay for the simultaneous determination of metoprolol and two main metabolites in human urine by solid-phase extraction and fluorescence detection

An improved, more efficient method for the determination of metoprolol and its two metabolites in human urine is reported. The simultaneous analysis of the zwitterionic metoprolol acidic metabolite (III, H117/04) with the basic metabolites alpha-hydroxymetoprolol (II, H119/66), metoprolol (I) and guanoxan (IV, internal standard) was achieved employing solid-phase extraction and isocratic reversed-phase HPLC. The analytes were extracted from urine (100 microliters) using C18 solid-phase extraction cartridges (100 mg), and eluted with aqueous acetic acid (0.1%, v/v)-methanol mixture (40:60, v/v, 1.2 ml). The eluents were concentrated (250 microliters) under vacuum, and aliquots (100 microliters) were analysed by HPLC with fluorescence detection at 229 nm (excitation) and 309 nm (emission) using simple isocratic reversed-phase HPLC (Novapak C18 radial compression cartridge, 4 microns, 100 x 5 mm I.D.). Acetonitrile-methanol-TEA/phosphate buffer pH 3.0 (9:1:90, v/v) was employed as the eluent (1.4 ml/min). All components were fully resolved within 18 min, and the calibration curves for the individual analytes were linear (r2 > or = 0.996) within the concentration range of 0.25-40.0 mg/ml. Recoveries for all four analytes were greater than 76% (n = 4). The assay method was validated with intra-day and inter-day variations less than 2.5%.

Lack of a pharmacologic interaction between rifabutin and methadone in HIV-infected former injecting drug users

Rifampin, an agent known to decrease the half-life of methadone, and rifabutin are two rifamycins that are structurally similar and share mechanisms of action. Hence the possibility of a drug-drug interaction between rifabutin and methadone was evaluated in 24 methadone-maintained, former injecting drug users infected with the human immunodeficiency virus. The study was an open-label, drug-drug interaction and safety trial in which patients were followed for 15 days. Each patient received rifabutin 300 mg as a single dose concomitantly with their individualized methadone dosage. No significant differences in methadone peak plasma concentration, time to peak plasma concentration, area under the plasma concentration-time curve, systemic clearance or renal clearance was observed in the presence of rifabutin. Seventy-five percent of the patients reported at least one symptom of narcotic withdrawal during the study, however, these symptoms were mild. A relationship between the development of narcotic withdrawal and methadone systemic exposure could not be established. Concurrent administration of rifabutin and methadone appeared to be safe in human immunodeficiency virus-infected injecting drug users maintained on stable doses of methadone and is not expected to produce any significant changes in the pharmacokinetics of methadone in these patients.

Effect of Oral Administration of Fennel (Foeniculum vulgare) on Ciprofloxacin Absorption and Disposition in the Rat

The aim of this study was to investigate the possibility of a drug‐drug interaction between ciprofloxacin and fennel (Foeniculum vulgare) in a rat model.

Efficient assay for the determination of atenolol in human plasma and urine by high-performance liquid chromatography with fluorescence detection

An efficient method for the determination of atenolol in human plasma and urine was developed and validated. alpha-Hydroxymetoprolol, a compound with a similar polarity to atenolol, was used as the internal standard in the present high-performance liquid chromatographic analysis with fluorescence detection. The assay was validated for the concentration range of 2 to 5000 ng/ml in plasma and 1 to 20 microg/ml in urine. For both plasma and urine, the lower limit of detection was 1 ng/ml. The intra-day and inter-day variabilities for plasma samples at 40 and 900 ng/ml, and urine samples at 9.5 microg/ml were <3% (n=5).

Utilization and Monitoring of Aminoglycosides in Oncology Patients at a Hong Kong Government Hospital

1. Fabre G, Julian B, Saint-Aubert B, Joyeux H, Berger Y. Evidence for CYP3A-mediated N-deethylation of amiodarone in human liver microsomal fractions. Drug Metab Dispos 1993;21:978-85. 2. Chow MSS. Intravenous amiodarone: pharmacology, pharmacokinetics, and clinical use. Ann Pharmacother 1996;30:637-43. 3. Andreasen F, Agerbaek H, Bjerregaard P, Grotzche H. Pharmacokinetics of amiodarone after intravenous and oral administration. Eur J Clin Pharmacol 1981;19:293-9. 4. Burger DM, Hoetelmans RMW, Koopmans PP, Meenhorst PL, Mulder JW, Hekster YA, et al. Clinically relevant drug interactions with antiretroviral agents. Antiviral Therapy 1997;2:149-65. 5. Product information. Norvir (ritonavir). Chicago: Abbott Laboratories, 1996.

A model based assessment of redistribution dependent elimination and bioavailability of rifabutin.

The autoinduction characteristic of rifabutin (RIF) following multiple oral dosing was investigated via pharmacokinetic modeling. A two-compartment model with first-order absorption was fit to plasma RIF data obtained from a study conducted in healthy normal volunteers following both a single and multiple oral doses. Parameter estimates showed an elimination rate constant (k10) of about 0.12-0.14 h-1 which was independent of the single or multiple-dosing condition. The lower-than-expected drug accumulation following multiple dosing seems to suggest that prolonged dosing perturbs the linear kinetic system. However, this analysis has shown no significant changes (p > 0.05) in the rate constants describing RIF absorption, tissue distribution/redistribution, and elimination. The mean rate of drug redistribution from the tissue compartment (k21; 0.04-0.06 h-1) was twofold to threefold lower than k10, and, with a large steady-state distribution volume (Vss/F after a single dose, 1630 L), RIF elimination appears to be dependent on drug redistribution. This hypothesis was further supported by a significant correlation (p < 0.01) between RIF tissue redistribution (k21) and terminal disposition phase rate (lambda z) constants. The redistribution dependent elimination of RIF also helps explain the stability of the terminal half-life under both single and multiple-dosing paradigms. Urinary excretion of RIF and its 25-O-deacetyl metabolite totalled less than 7% of the oral dose following single dosing, and decreased to about 4% after multiple dosing. For individual patients, the decrease in urinary recovery of the 25-O-deacetyl metabolite was directly proportional to the decrease in urinary RIF recovery. In addition, both estimates of the model intercepts (A and B) were lower following multiple dosing. Further analyses revealed a linear relationship between A and B intercepts, and also between the urinary RIF recovery and the B intercept. These relationships, in conjunction with the lack of significant increase in the rate of elimination, indicate that induction of presystemic extrahepatic metabolism and/or decrease in the extent of oral absorption may be the primary causes for the lower-than-expected systemic RIF plasma levels after multiple oral dosing.

Induction of hepatic and presystemic metabolism of antipyrine in the mice: Rifampicin versus rifabutin

SummaryThe effects of hepatic and presystemic enzyme induction on the bioavailability (F) and disposition of antipyrine after repeated rifampicin (RFM) and rifabutin (RBT) exposure were studied in mice. ICR mice were divided to receive 4 daily oral dosing of either the dosing vehicle or 50 mg/kg of REM or RBT. At the completion of rifamycin dosing, the pharmacokinetics of antipyrine were assessed following either a single 50 mg/kg oral dose or a 20 mg/kg intravenous dose. Blood samples were collected (n=4/timepoint) over a 6 h period. The content of P450 in the liver and small intestine (GI) was also assessed in parallel. Systemic antipyrine clearance (CL) increased from 31.8 ml/min/kg (controls) by 64% and 42% following repeated exposure to RFM and RBT, respectively. Estimate of F for antipyrine decreased from 0.97 in controls to 0.58 and 0.82 in animals treated with RFM and RBT, respectively. The content of P450 (nmol/mg protein) in the liver increased from 0.61 (control) to 1.36 following RFM and 0.82 for RBT, while no significant changes were observed for the GI tract. The i.v. dosing data confirmed the induction of antipyrine metabolism in the liver by both rifamycins yet the induction potential was approximately 1/3 lower for RBT. This difference was consistent with the changes observed in the hepatic P450 protein content, but this alone could not account for the reduction in the F for antipyrine. Therefore, predictions for changes in F of an interacting agent should not be judged solely on the basis of the metabolic status of the liver. The relative contribution of metabolic induction and presystemic drug loss to bioavailability / absorption should also be further delineated for its relevance to poly-pharmacy in patients likely to receive longterm rifamycin based treatment.