Pharmacokinetic study of all-trans-retinoyl-beta-D-glucuronide in Sprague-Dawley rats after single and multiple intravenous administration(s).

All-trans-retinoyl-beta-D-glucuronide (RAG) is an endogenous active metabolite of all-trans-retinoic acid (ATRA). In the present study, the pharmacokinetics of RAG was examined after the administration of a single intravenous does (5, 10, or 15 micromol/kg) and of multiple daily intravenous doses (5 micromol/kg) to rats for 8 days. The plasma concentrations of RAG and ATRA were measured by a reverse-phase HPLC method. A rapid distribution phase of approximately 1 h was observed in all of the rats after single or multiple doses. Thereafter, RAG was eliminated through a first-order process, in accord with a typical two-compartment first order pharmacokinetic profile. After single intravenous doses, the AUC of RAG increased proportionally with the dose and the clearance remained unchanged within the tested doses. There was no statistical significant difference in distribution rate constants from central compartment to peripheral compartment (K(12)) and from peripheral compartment to central compartment (K(21)) between different doses. However, as the dose increased from 5 micromol/kg to 10 micromol/kg, the volume of distribution at the steady state (V(ss)) and the volume of peripheral compartment (V(p)) decreased significantly (p < 0.05) from 1.290 +/- 0.269, 0.928 +/- 0.232. L/kg to 0.961 +/- 0.149, 0.647 +/- 0.107 L/kg, respectively. V(ss) and V(p) at a dose of 15 micromol/kg (0.924 +/- 0.187, 0.698 +/- 0.165 L/kg) were not significantly different from that at 10 micromol/kg. Thus, RAG might saturate the tissue-binding sites at higher doses. ATRA was detected as a metabolite of RAG at low levels (usually < 0.05 microM) only in the first 2 h after intravenous administration. RAG clearly was not extensively hydrolyzed to ATRA in our study. After multiple daily intravenous administration of RAG, the clearance (Cl) and the elimination rate constant (K(10)) remained unchanged (p > 0.05), indicating that long-term daily administration of RAG did not induce its accelerated metabolism. However, K(12), V(p), and V(ss) declined significantly (p < 0.05) from 1.67 +/- 0.54 h(-1), 0.928 +/- 0.232 L/kg, and 1.290 +/- 0.269 L/kg to 0.96 +/- 0.48 h(-1), 0.494 +/- 0.147 L/kg, and 0.818 +/- 0.187 L/kg, respectively. Therefore, long-term daily dosing of RAG seemed to decrease its distribution profile. Although the AUC of RAG did not change significantly after multiple dosing, the AUC of ATRA after RAG dosing significantly declined (p < 0.05) from 0.032 +/- 0.019 microM x h to 0.010 +/- 0.006 microM x h. The decline in the AUC of ATRA might reflect an increase in its uptake by tissue and/or in its metabolism. Because enhanced clearance is not associated with RAG after multiple administrations, RAG could be considered as an alternate to ATRA in appropriate clinical applications.

Kinetic study of a 2-hydroxypropyl-beta-cyclodextrin-based formulation of all-trans-retinoic acid in Sprague-Dawley rats after oral or intravenous administration.

all-trans-Retinoic acid (ATRA, vitamin A acid, or tretinoin) is a potent chemotherapeutic agent for the treatment of acute promyelocytic leukemia (APL). Its poor aqueous solubility not only affects its oral absorption but also prevents it from forming an aqueous parenteral formulation. Recently, we developed a water-soluble formulation of ATRA with 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD). In present study, this formulation was tested in Sprague-Dawley rats. Kinetic study of ATRA was carried out after oral or intravenous administration. Though there were no statistical differences in any of the estimated pharmacokinetic parameters between ATRA sodium salt and HPbetaCD-based ATRA after intravenous administration, inclusion of ATRA into HPbetaCD was found to greatly improve the oral absorption of ATRA.

Prejunctional and postjunctional inhibition of adrenergic transmission in the rat-isolated anococcygeus muscle by cimetidine.

1. Cimetidine and ranitidine can inhibit various cholinergic sites, which can account for some of their clinically documented adverse effects; ranitidine can also inhibit adrenergic transmission, closely resembling the action of guanethidine. The effects of cimetidine on adrenergic transmission in the rat isolated anococcygeus muscle (Acm) were therefore investigated. 2. The contractile (motor) responses of the Acm to electrical field stimulation (EFS; 20-30V, 10 s, 1 ms pulse width, every 2 min) at varying frequencies (Hz: 5, 10, 20) and to 3 microM noradrenaline (NA) were inhibited in a concentration-dependent manner by cimetidine (mM: 1, 2, 4, 8). Inhibition of the EFS-induced responses was inversely related to the stimulation frequency. 3. Cimetidine (nM: 2, 4, 8) produced a concentration-dependent and non-parallel shift of the NA cumulative log concentration-response curves (CRCs; curves 2, 3, 4) to the right of the control curve (curve 1); at the highest concentration (8 mM) used, cimetidine produced a 4.3-fold shift of curve 4 accompanied by a decline of 9.4 +/- 1.5% in the maximal response to NA (compared to essentially no change in maximal responses for the corresponding CRCs in the NA control series). Cimetidine therefore inhibited the postjunctional alpha-adrenoceptor sites. 4. The contractile responses of the Acm to EFS (i.e. prejunctionally mediated responses) were more sensitive to inhibition by cimetidine than the NA-induced (postjunctionally mediated) responses: 8 mM cimetidine inhibited the responses to EFS by about 97%, whereas the responses to NA were inhibited by only 41 +/- 5%.(ABSTRACT TRUNCATED AT 250 WORDS)

Dual action of ranitidine at cholinergic sites in the rat isolated anococcygeus muscle.

1. The effects of ranitidine on contractile responses of the rat isolated anococcygeus muscle to acetylcholine (ACh) and carbachol (CCh) were investigated. 2. Four consecutive cumulative concentration-response curves (CRCs) for ACh or CCh were constructed in the absence or presence of ranitidine. The mean EC50 values were determined from the individual CRCs and used for the calculation of the corresponding EC50 ratios. 3. Ranitidine (0.01, 0.05 and 0.5 mM) produced a progressively leftward shift of the ACh curves; the corresponding EC50 ratios obtained were 3.2 +/- 0.4, 5.7 +/- 0.5 and 9.4 +/- 1.4. Neostigmine 0.5 microM alone or in combination with ranitidine 0.1 mM produced very marked leftward shifts of the ACh curves (EC50 ratios 68.2 +/- 14.3 and 56.3 +/- 9.6 respectively). In contrast, ranitidine (0.05, 0.5 and 2 mM) produced a rightward and parallel shift of the CCh curves (EC50 ratios 1.0 +/- 0.1, 3.4 +/- 0.32 and 12.5 +/- 1.7 respectively). 4. Ranitidine can therefore mediate a dual action at cholinergic sites in the rat isolated anococcygeus muscle, actions which can be attributed to its inherent anticholinesterase and antimuscarinic activity. The relatively marked anticholinesterase action of ranitidine was rather surprising in view of the limited cholinergic innervation present in the rat anococcygeus muscle.

Cimetidine and ranitidine: a study of competitive and ion-channel blockade in the toad isolated rectus abdominis muscle.

Responses of the toad isolated rectus abdominis muscle to cumulative doses of carbachol were recorded in the absence or presence of varying concentrations of cimetidine or ranitidine. The corresponding cumulative log concentration-response curves for carbachol were then plotted for each antagonist studied. Cimetidine (1 mmol/l) produced a straight and parallel 1.8-fold shift of the carbachol curve to the right of the corresponding control curve with no significant change in the maximal response. Cimetidine, at doses of 2.5 mmol/l and 5 mmol/l, and ranitidine, at doses of 0.1 mmol/l, 0.25 mmol/l and 0.5 mmol/l, produced a concentration-dependent and non-parallel shift of the carbachol curve to the right of the corresponding control curve accompanied by a marked decline of maximal responses. The results provide further evidence that ion-channel block may be involved in the neuromuscular blockade produced by cimetidine or ranitidine, the latter being more potent in this respect. Competitive antagonism may also be partly responsible for cimetidine-induced neuromuscular blockade, especially at lower drug concentrations.