In vitro and in vivo studies of a new sustained release formulation of morphine. Discrepancies between the in vitro release and the in vivo absorption in dogs.

An in vivo preclinical study has been made of the oral absorption of morphine (CAS 57-27-2) from a new sustained release formulation (morphine-Eudragit L complex, MEC), which had shown good sustained release properties in in vitro dissolution studies. The absorption of morphine from capsules filled with morphine hydrochloride trihydrate (MHT) or MEC was compared in fasted and fed dogs. Mean plasma morphine concentrations obtained after administration of MHT and MEC to fasted dogs were similar, and no statistically significant differences were found in the pharmacokinetic parameters of morphine (Cmax, Tmax and area under the plasma morphine concentration versus time curve from time zero to the last time with a detectable concentration of morphine). When MHT and MEC were administered to fed animals, mean plasma morphine concentrations were again similar for both formulations, without statistically significant differences in the pharmacokinetic parameters of morphine. These results contrast with those obtained in vitro, and indicate the limited usefulness of in vitro assays for this kind of sustained release formulations in which pH and ionic strength are important factors for drug release from the polymeric structure. The plasma morphine concentrations obtained in fed dogs were generally lower than in fasted dogs, though they were detectable for a longer time, until 10 h after dosing, in contrast to up to 6 h in fasted dogs. It is postulated that the apparently prolonged absorption of morphine in fed dogs may be due to the enterohepatic recycling of the drug (excreted in bile as glucuronide, hydrolysed back to the parent compound in the intestine, and then reabsorbed) as a consequence of gallbladder emptying induced by food.

Effect of cytochrome P450 inhibitors (diethyl dithiocarbamate, ketoconazole and grapefruit juice) on the pharmacokinetics of all-trans-retinoic acid.

Diethyl dithiocarbamate (DEDTC) has been reported to be a more powerful inhibitor of all-trans-retinoic acid (ATRA) in vitro metabolism than the well-established cytochrome P450 (CYP) inhibitor ketoconazole (KC). In recent years grapefruit juice (GJ) has been shown to be able to increase the oral bioavailability of several drugs by inhibiting intestinal CYP. This study investigated the in vivo effect of these CYP inhibitors on the pharmacokinetics of ATRA. The latter was administered to rats as a constant-rate intravenous (i.v.) infusion (0.48 mg h(-1) kg(-1)) during 10 h and orally (1.6 mg kg(-1)). DEDTC (320 mg kg(-1) x 2 i.v., 6.4 and 32 mg kg(-1) per os (p.o.)) did not change the ATRA concentration-time profiles, whereas KC (320 and 32 mg kg(-1) p.o.)--with i.v. infused or orally dosed ATRA--increased the mean concentration-time curve value by 160% and 78%, respectively. A high dose of DEDTC (320 mg kg(-1) p.o.) caused a marked decrease in plasma levels of ATRA. GJ (6.4 ml kg(-1) p.o.) did not affect the plasma levels of ATRA. It is concluded that the in vivo effect of CYP inhibitors (DEDTC and KC) on the elimination rate of ATRA is qualitatively different from that expected from in vitro studies.

Pharmacokinetics of the time-dependent elimination of all-trans-retinoic acid in rats.

The time-dependent elimination kinetics of all-trans-retinoic acid (ATRA) has been associated with autoinduction of its metabolism and has led to the hypothesis that rapid development of acquired clinical resistance to ATRA may be prevented by coadministration of metabolic inhibitors. This study in rats was performed to investigate the pharmacokinetics and onset of time-dependent elimination of ATRA, with the purpose of establishing an animal model suitable for in vivo preclinical studies of compounds capable of inhibiting ATRA metabolism. After the intravenous (IV) bolus administration of single doses of ATRA (1.60 mg kg(-1) and 0.40 mg kg(-1)), the plasma concentration-time curves showed an accelerated decline at 180 minutes after dosing. The plasma clearance (Cl) of ATRA, determined after IV administration of a second dose (1.60 mg kg(-1)), at 180 minutes was greater than Cl after a single dose, thus indicating the existence of a time-dependent elimination process detectable 180 minutes after administration of the first dose. Such time-dependent elimination was confirmed by means of an IV constant-rate infusion of 0.48 mg h(-1) kg(-1) of ATRA during 10 hours. Peak plasma ATRA concentration was achieved at 180 minutes, after which the plasma concentration decreased to reach a much lower apparent steady-state drug concentration at 420 minutes. The area under the plasma concentration-time curve (AUC) obtained after oral administration of a second ATRA dose (1.60 mg kg(-1)) was approximately 8% of the AUC obtained after a single oral dose; consistent with a time-dependent increase in the elimination of ATRA, as was observed after IV administration.

Effect of cyclosporine A on the tissue distribution and pharmacokinetics of etoposide.

PURPOSE: Cyclosporine A (CyA) is able to inhibit P-glycoprotein (P-gp) and to increase cytotoxicity of some anticancer drugs, including etoposide. However, the effect of CyA on the distribution of etoposide in normal tissues, which could affect their toxicity, has not been studied extensively. The purpose of this study was to investigate the effect of CyA on the pharmacokinetics and tissue distribution of etoposide in rats. METHODS: Etoposide was administered as an i.v. bolus injection (3 mg) or as a constant-rate i.v. infusion (8 mg/h) 1 h after the beginning of infusion of CyA or saline. Animals were killed 1 h after the bolus administration or after the beginning of infusion of etoposide, and plasma and tissue (testicle, muscle, heart, lung, spleen, kidney, liver, colon, and intestine) concentrations of etoposide, blood concentrations of CyA were determined. All analyses were performed by HPLC. RESULTS: Infusion of CyA (1 mg/h) in rats treated with an i.v. bolus of etoposide caused a decrease in the plasma clearance (5.4+/-2.1 vs 9.3+/-2.4 ml/min), and an increase in plasma and tissue concentrations of etoposide, but the tissue-to-plasma concentration ratios of etoposide were not affected. When etoposide was infused at a constant rate to reach a steady-state plasma level, coinfusion of CyA (10 mg/h) also caused a decrease in the plasma clearance (4.8+/-1.5 vs 9.8+/-4.7 ml/min), and an increase in plasma and tissue concentrations of etoposide. Only lung and spleen showed tissue-to-plasma ratios of etoposide significantly higher than obtained in rats coinfused with saline, but the differences were small. CONCLUSIONS: The higher tissue concentrations of etoposide caused by CyA administration were mainly a direct consequence of the higher plasma concentration resulting from a decrease in the clearance of etoposide rather than a consequence of changes in the tissue distribution of etoposide. Extrapolation of the results obtained in rats to clinical practice suggests that the coadministration of etoposide and CyA would not lead to an increase in the toxicity of etoposide if the dose were decreased in the same proportion as clearance of etoposide is decreased by CyA administration.