Junko Ishizaki

Relationships in the Structure–Tissue Distribution of Basic Drugs in the Rabbit

The relationship between the tissue-to-plasma partition coefficients (Kp) and drug lipophilicity was investigated using highly lipophilic drugs with apparent partition coefficients of 150 or above in an octanol–water system at pH 7.4. Ten clinically popular basic drugs with different dissociation coefficients (pKa) and lipophilicity were used. The Kp values were determined in nondisposing organs after the i.v. administration of individual drugs in rabbits. The free fraction in plasma and the blood-to-plasma concentration ratio were determined in vitro. Then the tissue-to-plasma ratios of nonionized and unbound drug concentrations (Kpfu) were calculated from Kpf (ratio of unbound drug). The true octanol–water partition coefficient of the nonionized drugs (P) was used to analyze the Kpf and Kpfu. In all tissues, log Kpfu was more highly correlated with log P than log Kpf.

Modulation of mdr1a and CYP3A gene expression in the intestine and liver as possible cause of changes in the cyclosporin A disposition kinetics by dexamethasone

We investigated the effect of dexamethasone (DEX) on the disposition kinetics of cyclosporin A (CyA) and the mechanism of this drug interaction. Rats were treated with DEX (1 or 75mg/kg per day, i.p.) once a day for 1-7 days, and the blood concentration of CyA was measured after an i.v. or p.o. dose of CyA (10mg/kg) at 1.5hr after the last DEX treatment. In rats treated with a low dose of DEX (1mg/kg), the blood concentration of CyA after i.v. administration was unchanged compared with that of untreated rats, whereas the blood concentration after oral administration was significantly decreased, and this decrease was dependent on the duration of DEX administration. The total clearance (CL(tot)) of CyA was unchanged, but the bioavailability was significantly decreased to about one-third of that in DEX-untreated rats after 7 days of DEX treatment. At this time, the expression of mdr1a mRNA and P-gp in the liver and intestine was increased, whereas CYP3A2 was unaffected at both the mRNA and protein levels. In rats treated with a high dose of DEX (75mg/kg), the blood concentration of CyA was significantly decreased after both i.v. and p.o. administrations compared with those of untreated rats. The bioavailability of CyA was decreased, and the CL(tot) was significantly increased. The P-gp and CYP3A2 in the liver and intestine were increased at both the mRNA and protein levels. Our results indicate that the drug interaction between CyA and DEX is a consequence of modulation of P-gp and CYP3A2 gene expression by DEX, with differential dose-dependence.

Effect of Meropenem on Disposition Kinetics of Valproate and Its Metabolites in Rabbits

AbstractPurpose. We investigated the effect of meropenem (MEPM) on the disposition kinetics of valproate (VPA) and its metabolites in rabbits. Methods. Rabbits were given 75 mg/kg VPA intravenously with or without 300 mg/kg MEPM. Results. The plamsa total clearance of VPA was significantly increased to about 1.5 times the control (6.09 mL/min/kg vs. 4.28 mL/min/kg) by MEPM (P < 0.05). The values of the area under the plasma concentration-time curve (AUC) of 2-en-VPA, a product of β-oxidation, and VPA-glucuronide (VPA-G) were significantly decreased to about 55% and 78% of the control, respectively (P < 0.05). The cumulative urinary excretions of VPA in the control and MEPM-treated groups were 0.54% and 0.62% of the dose, respectively, whereas those of VPA-G were 45.6% and 62.5%, respectively. The urinary excretion of VPA-G was significantly increased by MEPM (P < 0.05). Further, in the case of 33.8 mg/kg VPA-G administered intravenously the AUC value of VPA-G was unchanged by MEPM, whereas that of the generated VPA was significantly decreased to about half of the control. Conclusions. The increase of the total clearance of VPA caused by MEPM appears to be a consequence of increased renal clearance of VPA-G, as well as suppression of VPA-G hydrolysis in the liver.

Effect of betamethasone phosphate loaded polymeric nanoparticles on a murine asthma model

Although inhaled steroids are the treatment of first choice to control asthma, administration of systemic steroids is required for treatment of asthmatic exacerbation and intractable asthma. To improve efficacy and reduce side effects, we examine the effects of betamethasone disodium phosphate (BP) encapsulated in biocompatible, biodegradable blended nanoparticles (stealth nanosteroids) on a murine model of asthma. These stealth nanosteroids were found to accumulate at the site of airway inflammation and exhibit anti-inflammatory activity. Significant decreases in BALF eosinophil number were maintained for 7 days with a single injection of nanosteroids containing 40 microg BP. Airway responsiveness was also attenuated by the injection of stealth nanosteroids. A single injection of 40 microg of free BP and 8 microg of free BP once daily for 5 days did not show any significant effects. We conclude that stealth nanosteroids achieve prolonged and higher benefits at the site of airway inflammation compared to free steroids.

Contribution of lysosomes to the subcellular distribution of basic drugs in the rat liver

AbstractPurpose. We examined the subcellular distribution of the basic drugs, chlorpromazine (CPZ), imipramine (IMP) and biperiden (BP), in rat liver, and evaluated the contribution of lysosome (Lys) to their intracellular distribution in comparison with that of mitochondria (Mit). Methods. In an in vivo distribution, the concentrations of CPZ, IMP and BP in the liver subcellular fractions were determined. In an in vitro study, uptake of [3H]IMP into Lys and Mit fractions was determined in the presence or absence of several agents. Results. The distribution of these drugs 10 min after administration was quite similar. However, the relative specific contents (the drug concentration per protein of each fraction divided by that of the total homogenate) in Lys were 7.3, 9.6 and 4.2, respectively for CPZ, IMP and BP, whereas those in the other organella were only 0.4 ~ 1.7. In an in vitro uptake study, the dose response of IMP uptake into Lys was biphasic, while that into Mit fractions was monophasic. The binding of IMP to the high affinity sites of Lys was pH dependent and disappeared in 50 mM NH4C1 or 50 µM CPZ, both of which increased the intralysosomal pH. the low affinity sites were not affected by these drugs. Conclusions. The results indicated that Lys has the highest affinity for the basic drugs in the liver and that its contribution to their subcellular distribution depends on the intralysosomal pH, which is also affected by these drugs. The importance of these effects may become significant in combination therapy using various basic drugs.

Selective drug delivery to bone using acidic oligopeptides

Bone is susceptible to a range of diseases, similar to other tissues. However, it is generally difficult to deliver and retain drugs in the bone. Bone is composed of unique materials such as the inorganic compound hydroxyapatite (HAP) and bone matrix proteins, which are quite different from the components of other tissues. Among them, HAP may be a promising target for selective drug delivery to bone. Now, two promising methods have been reported for selective drug delivery to the bone as a target HAP. One is a class of molecules known as bisphosphonates. Systemic administration of bisphosphonates commonly results in 20– 50% deposition of the molecule at bone tissues, with minimal accumulation at other sites [1]. These compounds not only show an antiosteoporosis effect by themselves [2] but are useful as the drug delivery carrier to the bone [3–6]. Another is the oligopeptide, having high affinity to the bone, described in this review. The structures of several bone noncollagenous proteins that bind to HAP have a repeating sequence of acidic amino acids (Asp, Glu), which may serve as a HAP-binding site. Osteopontin and bone sialoprotein, two major noncollagenous proteins in bone, have L-Asp and L-Glu repetitive sequences, respectively (Fig. 1), and rapidly bind to HAP after they are secreted in osteoblastic cell culture [7–9]. Thus, these acidic oligopeptides are candidate bone-targeting carriers. It was hypothesized that, after systemic administration, a drug tagged with such an oligopeptide would be selectively delivered and bind to bone, where the active drug would be released gradually during bone remodeling processes. This review describes the properties of acidic oligopeptides and introduces the tagging of three model drugs, estradiol, quinolone antibiotics, and tissue-nonspecific alkaline phosphatase (TNSALP), with an acidic oligopeptide to examine the clinical feasibility of the acidic oligopeptide strategy for selective drug delivery to bone.

Disposition kinetics of taxanes after intraperitoneal administration in rats and influence of surfactant vehicles.

Rats were intraperitoneally administered 40 mg kg−1 of paclitaxel or docetaxel dissolved in various drug solutions. The drug solutions were prepared using 20 mL of saline, adding 4.2% Cremophor EL (crEL) for paclitaxel (TXL), and 1.5% Polysorbate‐80 (PS‐80) (TXT), 7.5% PS‐80 (TXT+PS‐80) or 4.2% crEL (TXT+crEL) for docetaxel. The apparent first‐order absorption rate constant from the peritoneal cavity (ka) of TXL was about one‐twentieth of that of TXT. The ratio of the area under the concentration‐time curve of drug in plasma over that in ascites for TXL was about one‐third of that of TXT. The values of the above ratio and the ka of TXT+PS‐80 and TXT+crEL were similar to those of TXL. After intraperitoneal administration, the values of the blood‐to‐plasma concentration ratio in the four groups were similar and independent of time. In the in‐vitro study, PS‐80 and crEL caused similar, concentration‐dependent decreases of drug permeation into red blood cells after a 15‐min incubation of rat blood with 10 μg mL−1 of TXL. We demonstrated that the disposition kinetics of taxanes after intraperitoneal administration to rats was strongly influenced, in a concentration‐dependent manner, by the surfactant vehicle used, crEL or PS‐80.

Relationships between the Hepatic Intrinsic Clearance or Blood Cell‐Plasma Partition Coefficient in the Rabbit and the Lipophilicity of Basic Drugs

The relationships between drug lipophilicity and hepatic intrinsic clearance (CLint,h) or red blood cell‐plasma partition coefficients (D) have been elucidated for ten highly lipophilic basic drugs with apparent octanol‐water partition coefficients at pH 7.4 (Papp, oct) of 150 or above.

Prediction of Changes in the Clinical Pharmacokinetics of Basic Drugs on the Basis of Octanol‐Water Partition Coefficients

A physiologically based pharmacokinetic model for basic drugs has been established on the basis of octanol‐water partition coefficients of the non‐ionized, unbound drugs (Poct).

Involvement of α1-acid glycoprotein in inter-individual variation of disposition kinetics of ropivacaine following epidural infusion in off-pump coronary artery bypass grafting

The influence of drug interaction and protein variants on the binding disposition of ropivacaine to α1‐acid glycoprotein (AGP) was examined. The subjects were five patients who received epidural infusion of ropivacaine for 24–54 h in off‐pump coronary artery bypass grafting followed by drug combination therapy, and 10 healthy volunteers.