Hiroshi Iguchi

Pharmacokinetics and disposition of 4′-O-tetrahydropyranyladriamycin in mice by HPLC analysis

SummaryThe plasma level of 4′-O-tetrahydropyranyladriamycin (THP) declined rapidly after IV injection to mice, with a t1/2(α) of 0.453 min. Only 1.2 μg/ml THP was detected 2 min after injection of 5 mg/kg. The drug was immediately transferred to various tissues, where the drug levels were much higher than the plasma concentration. In the lung and spleen, 8.26 and 13.6 μg/g THP was present, respectively, 2 h after administration. Major metabolites of THP were 13-dihydro-THP, ADM, 7-deoxyadriamycinone, and 7-deoxy-13-dihydro-adriamycinone. Only 1.12% of the dose had been recovered in the urine by 48 h after injection as THP and its metabolites, according to analysis by HPLC fluorospectroscopy. The observed disposition of THP was compared with that of adriamycin (ADM). The plasma disappearance and tissue transfer of THP were faster than those of ADM. THP levels in the spleen and lung were higher and those in the heart and liver were lower than the corresponding ADM levels. Drug levels declined more quickly in most tissues in the case of THP than of ADM. Tissue distributions after single bolus and multiple injections were also compared and discussed.

Pirarubicin-induced Endothelium-dependent Relaxation in Rat Isolated Aorta

Abstract— The mechanism of relaxation produced by pirarubicin [(2″R)‐4′‐O‐tetrahydropyranyladriamycin, THP] has been studied in rat isolated aorta. THP (1·5 × 10−6–4·5 × 10−5 m) markedly relaxed contractions induced by noradrenaline (10−7 m) in the aorta with endothelium, but not in that without endothelium. The relaxation induced by 1·5 × 10−5 m THP was inhibited by methylene blue (5 × 10−6 m), hydroquinone (10−4 m), phenidone (5 × 10−5 m), haemoglobin (10−6 m) and p‐bromophenacyl bromide (5×10−5 m), but not by indomethacin (2·5 ×10−5 m). The relaxation induced by THP (1·5 × 10−7 − 4·5 × 10−5 m) was inhibited by NG‐nitro‐l‐arginine (10−5 m), but enhanced by superoxide dismutase (10 units mL−1) or by L‐arginine (10−2 m). However, the THP‐induced relaxation was not inhibited by various receptor antagonists such as atropine (10−6 m), cimetidine (10−5 m), diphenhydramine (3 × 10−6 m) and [D‐Pro4, D‐Trp7,9,10]‐substance P(4–11) (1·5 × 10−6 m). In fifteen anthracycline analogues, THP and 13‐dihydropirarubicin (both with a tetrahydropyranyl group) produced endothelium‐dependent relaxations. These results suggest that the THP‐induced relaxation which is probably mediated by endothelium‐derived relaxing factor (EDRF) was not produced by an activation of muscarine, histamine H1 or H2, or substance P receptor, and further that the tetrahydropyranyl group must play an important role in the THP‐induced relaxation.

Effects of pirarubicin, an antitumor antibiotic, on the cardiovascular system

SummaryIn the present study we examined the effects of pirarubicin [(2″R)-4′-0-tetrahydropyranyladriamycin, THP] on a cardiovascular system. An injection of THP (0.39–3.13 mg/kg, i. v.) reduced the mean blood pressure and caused an increase in the respiratory air rate in anesthetized rats. At 1.5×10−6–1.5×10−5m, THP markedly relaxed a contraction induced by 10−7m norepinephrine in rat aorta with endothelium but not in that without endothelium. At a dose of 0.02–0.5 mg, THP produced an increase in the contractile force and the perfusion flow of isolated perfused guinea pig hearts. At a higher concentration (4.5×10−5–1.5×10−4m), it produced a slight increase in the contractile force of the left atria in guinea pigs. This positive inotropic action of THP was inhibited by diphenhydramine (10−6–5×10−5m), chlorpheniramine (3×10−7–3×10−5m), and tripelennamine (3×10−7–3×10−5m) but not by propranolol (10−6m), cimetidine (10−5m), diltiazem (10−6m), or ryanodine (10−8m). THP given i. v. at 2.5 mg/kg elevated the plasma histamine level in anesthetized dogs. From these data, we conclude that THP mainly relaxed the rat aorta in the presence of endothelium and that at higher concentrations, it increased the contractile force in the cardiac muscle, probably mediated through the release of histamine.

Effects of pirarubicin in comparison with epirubicin and doxorubicin on the contractile function in rat isolated cardiac muscles.

1. We have examined the effects of pirarubicin (THP), compared with epirubicin (EPI) and doxorubicin (DXR), on the contractile function in papillary muscles isolated from rats. 2. In in vivo experiments, in which the rat was treated once a week for 4 weeks with DXR (total dose 10 mg/kg) and thereafter once a week for 4 weeks with THP, EPI or DXR (total dose 10 mg/kg), a positive instead of negative force-frequency relationship was observed in the muscles treated with EPI and DXR, but not with THP, and an increase in contractile response to extracellular Ca2+ was observed more markedly in the muscles treated with DXR than in those treated with EPI and THP. 3. In in vitro experiments, in which the muscle preparations were incubated with the drugs at 100 or 200 microM for 2 hr, EPI and DXR caused a negative inotropic effect and a prolongation of tension duration, while THP caused a slight positive inotropic effect and a slight prolongation of tension duration. 4. Furthermore, a decrease in the potentiated postrest contraction was observed more markedly in the muscles incubated with EPI and DXR at 200 microM than in those with THP. 5. These results suggest that both EPI and DXR show a cardiotoxicity by impairing the function of cardiac sarcoplasmic reticulum, and that the switching of the treatment from DXR to THP produces less impairing effects.

A possible mechanism of endothelium-dependent relaxation induced by pirarubicin and carbachol in rat isolated aorta

Abstract— The mechanism of endothelium‐dependent relaxation induced by pirarubicin, (2″R)‐4′‐O‐tetrahydropyranyladriamycin, THP, or carbachol was investigated in the rat isolated aorta. The relaxant effect of THP (1·5 × 10−6‐4·5 × 10−5 m) or carbachol (10−8‐10−4 m) on the aorta with endothelium was decreased by lowering Ca2+ in the medium. The relaxation induced by THP was not inhibited by pretreatment with verapamil (10−6–10−5 m), and that induced by carbachol was only partially inhibited. However, on replacement of all but 20 Mm Na+ with either Li+ or choline, the THP‐ or carbachol‐induced relaxation was inhibited. Furthermore, the relaxing effect of THP or carbachol was inhibited by pretreatment with amiloride (10−4‐3 × 10−4 m), with ouabain (10−4‐10−3 m), or with K+‐depletion. These results suggest that the THP‐ or carbachol‐induced relaxation depending on endothelium was affected by modifying the calcium ion concentration, and that a Na+–Ca2+ exchange process is involved.