ABSTRACT
Penclomedine is a multi-chlorinated alpha-picoline derivative that has demonstrated activity in several murine breast cancer models and is currently in clinical testing for use against solid tumors. This study evaluates the metabolism of penclomedine in several in vitro hepatic models, including microsomes, fresh liver slices, and the isolated perfused rat liver (IPRL). Both human and mouse liver slices as well as human and mouse liver microsomes under aerobic conditions resulted in limited metabolism of penclomedine to several oxidized metabolites, including penclomic acid, 4-demethylpenclomic acid, and 4-demethylpenclomedine. Microsomes under anaerobic conditions vigorously produced mainly reduced metabolites, primarily penclomedine dimers. This is in contrast to in vivo data, which showed rapid metabolism of penclomedine to primarily 4-demethylpenclomedine. The IPRL preparation, however, metabolized 50 microM penclomedine 90% within 90 min, producing primarily 4-demethylpenclomedine and penclomic acid. These were formed in roughly equimolar amounts and did not undergo significant further metabolism over 4 hr. Numerous highly polar biliary metabolites were also found. The IPRL preparation thus seems to most accurately reflect the in vivo situation.
Subject(s)
Antineoplastic Agents/metabolism , Liver/metabolism , Picolines/metabolism , Animals , Female , Humans , In Vitro Techniques , Male , Mice , Rats , Rats, Sprague-DawleyABSTRACT
Arteether (AE) is primarily deethylated to dihydroqinghaosu (DQHS) in rats and humans. Conversion of AE to DQHS was impaired in microsomes from rats infected with Plasmodium berghei. The Km for AE was 175.1 +/- 49.1 and 124.4 +/- 115.1 mumol/l, and Vmax was 2.24 +/- 0.45 and 1.22 +/- 0.67 nmol AE formed/mg protein/min in control and infected microsomes (p < 0.05), respectively. Calculated intrinsic clearance (CLint = initial Vmax/Km) for AE was only 4% lower in infected microsomes. Apparent pharmacokinetic parameter estimates for AE using the isolated perfused rat liver demonstrated no differences (p > 0.05) in volume of distribution, clearance, and half-life between normal and infected animals. Malaria infection resulted in decreased biliary excretion of free AE and DQHS. The majority of AE is eliminated via biliary excretion of conjugated DQHS, which is approximately 500-fold higher than free DQHS and 75-fold higher than free AE on a molar basis.
Subject(s)
Antimalarials/pharmacokinetics , Artemisinins , Malaria/metabolism , Plasmodium berghei , Sesquiterpenes/pharmacokinetics , Animals , Antimalarials/pharmacology , Antimalarials/therapeutic use , Area Under Curve , Bile/metabolism , Chromatography, High Pressure Liquid , Cytochrome P-450 Enzyme System/metabolism , Half-Life , Isotope Labeling , Liver/drug effects , Liver/enzymology , Malaria/drug therapy , Male , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , NADPH-Ferrihemoprotein Reductase/metabolism , Perfusion , Rats , Rats, Sprague-Dawley , Sesquiterpenes/metabolism , Sesquiterpenes/pharmacology , Sesquiterpenes/therapeutic use , Tissue DistributionABSTRACT
Halofantrine and mefloquine are antimalarial drugs used in the treatment of malaria, including that caused by chloroquine-resistant Plasmodium falciparum. Reports of drug-associated adverse reactions, including sudden death in one patient, have prompted concerns over the safety of halofantrine and the potential for drug-drug interactions. We used the isolated perfused rat liver (IPRL) model to investigate a possible hepatic metabolic or pharmacokinetic drug-drug interaction between halofantrine and mefloquine. Pharmacokinetic parameter estimates for halofantrine in the IPRL reflected the pattern seen in in-vivo studies with doses comparable with clinical doses. Halofantrine parameter estimates (mean +/- s.d.) were: volume of distribution (Vd), 7.53 +/- 1.45 mL (g liver)-1; clearance (CL), 0.11 +/- 0.07 mL min-1 (g liver)-1; initial distribution half-life (initial t1/2), 14.62 +/- 2.38 min; terminal half-life (terminal t1/2), 138.7 +/- 178.8 min; AUC 606 +/- 194 mg mL-1 min-1 (g liver)-1; elimination rate constant (Ke), 0.0135 +/- 0.012 min-1. Prior dosing with mefloquine did not affect halofantrine perfusate pharmacokinetic parameter estimates of Vd, Ke, initial and terminal t1/2 (P > 0.05). A single dose, short term (4-6 h) interaction showed significant changes in the perfusate clearance of halofantrine in mefloquine-pretreated livers using higher doses of halofantrine. Substantial changes were seen in bile production (P < 0.05) and biliary clearance (P < 0.05) of halofantrine in mefloquine-pretreated livers. These findings may have clinical implications in models utilizing multiple drug dosages or in patients with severe malaria who have disease-related cholestasis.
Subject(s)
Antimalarials/pharmacology , Liver/drug effects , Mefloquine/pharmacology , Phenanthrenes/metabolism , Animals , Antimalarials/metabolism , Area Under Curve , Drug Interactions , In Vitro Techniques , Liver/metabolism , Male , Metabolic Clearance Rate , Perfusion , Rats , Rats, Sprague-DawleyABSTRACT
Neuroleptic malignant syndrome (NMS) is a potentially fatal disease process characterized by hyperthermia, altered mental status, muscular rigidity, and autonomic instability. This syndrome is most often seen in patients who are taking neuroleptics and other psychoactive medications. Primary care physicians are often the first providers to see patients with this syndrome and must be alert to its potential diagnosis. Treatment should be immediate and consists of discontinuing the neuroleptic medication; supporting pulmonary, cardiovascular, and renal functions, and using bromocriptine and/or dantrolene.
