The population pharmacokinetic analysis of olmesartan showed that: (i) severe renal impairment (serum creatinine >265 micromol/L [approximately 3 mg/dL]) could cause a clearance decrease of > or =30%; (ii) older age, lower bodyweight and being female were determinants of lower clearance but their effects on olmesartan clearance were within 20%; (iii) no statistically significant difference in clearance was found between Westerners and Japanese.

No abstract

Wehave studied an ester prodrug of a carbapenem to develop a potent orally active /Mactam antibiotic. A variety of l/?-methylcarbapenem derivatives have been synthesized. We have found that some derivatives having an amide group in the C-2 side chain show potent and well balanced antibacterial activities as well as high stability against dehydropeptidase-I. Oral absorption of derivatives has been optimized by modifying the C-3 ester promoiety. Pivaloyloxymethyl (li?,5S,6S)-6-[(JR)-l-hydroxyethyl]-l-methyl-2-[(jR)-5-oxopyrrolidin-3-ylthio]-l-carbapen-2-em-3-carboxylate, CS-834, has been selected as the most promising compound for further evaluation. An orally active antibiotic with potent activity is of much interest in the clinical realm because oral administration and lower dosage are advantageous for patients. Carbapenems are the most potent jS-lactam antibiotics which have a broad antibacterial spectrum and potent bactericidal activities against both Gram-positive and-negative organisms.1>2) They are highly resistant to hydrolysis by a variety of /Mactamases. So far, imipenem,3) panipenem4) and meropenem5)have been launched on the market, and several compounds are currently under clinical evaluation.6~8) However, most compoundshave been developed for parenteral use, and none for the practical purpose of oral administration. Currently, tricyclic /Mactam antibiotics, GV-1 04326 and its ester GV-118819, have been developed. GV-118819 is now under clinical study as an oral antiinfective drug.9-ll)

The pharmacokinetic behavior of panipenem (PAPM)-betamipron (BP), a new carbapenem, in humans was successfully predicted from data collected from six animal species. PAPM and BP were biphasically eliminated from plasma after intravenous (i.v.) administration of PAPM-BP to mice, guinea pigs, rats, rabbits, monkeys, and dogs. Elimination rates of PAPM and BP were correlated with animal size: the larger the animal was, the slower the elimination was. As for PAPM and BP, log-log plots of total plasma clearance (CLt.0) versus body weight and log-log plots of distribution volume at steady state (Vss) versus body weight for six animal species were linear, with high correlation coefficients. These allometric equations were extrapolated to predict CLt.0 and Vss for PAPM and BP in humans. In addition, concentration in plasma-time profiles for humans were predicted by using two-exponent equations fitted to the complex Dedrick plot of animal data. Predicted values for CLt1t and Vss for PAPM and BP in humans agreed well with observed values in humans given 750/750 mg of PAPM-BP as an i.v. drip infusion for 30 min. Predicted concentration in plasma-time profiles for humans approximated observed profiles. Thus, the pharmacokinetics of PAPM-BP extrapolated well from animal species to humans when allometric equations and the complex Dedrick plot were used.Panipenem (PAPM)-betamipron (BP) is a combination of a newly developed carbapenem antibiotic (PAPM) and a renal anion transport inhibitor (BP) in a ratio of 1:1 (wt/wt) (Fig.

The effects of i.v. formulations on the pharmacokinetics were examined for two antitumor agents with different lipophilicities: rhizoxin and palmitoyl-rhizoxin (RS-1541). Blood disposition and tissue distributions in rats were evaluated using three formulations: polyethylene glycol 400 (PEG)/dimethylacetamide (DMA) solution, colloidal solution, and lipid emulsions composed of dioctanoyl decanoyl glycerol (ODO) and polyoxyethylene-(60)-hydrogenated castor oil (HCO-60). The effects of emulsion particle size on the pharmacokinetics were also investigated. Rhizoxin rapidly disappeared from the plasma and showed high distribution in the tissues, and in vitro rapidly degraded in the plasma independent of the formulations used. In in vitro plasma, rhizoxin was easily released from the emulsion particles. In contrast to rhizoxin, the pharmacokinetics of RS-1541 with greater lipophilicity changed considerably depending on the formulations. The emulsions showed high and sustained plasma concentrations for RS-1541. RS-1541 was stably incorporated in the emulsion droplets and protected from the degradation when it was applied as an emulsion. Tissue distributions of RS-1541 in rats after an injection as lipid emulsion were strongly affected by the emulsion particle size. Small size emulsions (100-110 nm) showed the highest plasma concentrations of RS-1541, though they were unable to suppress distributions of the drug in peripheral tissues. Emulsions larger than 200 nm (approx.) in size, on the contrary, effectively inhibited the drug from entering the bone marrow, small intestine and other non-reticuloendothelial system (non-RES) organs, where many cytotoxic compounds showed undesired toxicities. These results indicate that the lipid emulsions composed of ODO and HCO-60 could be a promising and effective DDS carrier for RS-1541, which is highly lipophilic and stabilized in the emulsions. This was not the case for rhizoxin, however, which was less lipophilic than palmitoyl analogue RS-1541. The work described herein has demonstrated that by properly selecting the particle size, these lipid emulsions can control the behavior of a drug in the body.