Drug metabolism and disposition : the biological fate of chemicals
-
Drug Metab. Dispos. · Jul 1995
Plasma and tissue disposition of paclitaxel (taxol) after intraperitoneal administration in mice.
The pharmacokinetics of single intraperitoneal doses of paclitaxel (18 and 36 mg/kg) in mice were investigated in the present study. The analysis of drug concentrations by HPLC indicated that the plasma Cmax (13.0 +/- 3.1 and 25.7 +/- 2.8 micrograms/ml, respectively) were reached at the 2nd hr. The values of CL were low (0.06 and 0.1 ml/min, respectively), and t1/2 beta values of 3.0 and 3.7 hr were found, after 18 and 36 mg/kg, respectively. ⋯ In the case of the colic tissue, paclitaxel Cmax were 14.4 +/- 0.8 and 32.8 +/- 3.5 micrograms/g at the 3rd hr, respectively, with sustained drug levels still detectable 24 hr after treatment. Paclitaxel Cmax values of 12.7 +/- 3.0 and 53.4 +/- 5.6 micrograms/g were detected in the ovary after 18 and 36 mg/kg, respectively. The overall results provide evidence that, after intraperitoneal administration, paclitaxel concentrates in peritoneal organs; however, the intraperitoneal route does not prevent systemic drug exposure, allowing high and sustained levels of paclitaxel also in several extraperitoneal tissues.
-
Sevoflurane [CF3-CH(OCH2F)-CF3] is biotransformed to inorganic fluoride (F-) and hexafluoroisopropanol, which forms a glucuronide conjugate. Although sevoflurane may be used in newborns without fully developed biotransformation activity, studies were performed using liver slices from rat neonates to determine sevoflurane disposition. Sevoflurane was vaporized in sealed roller culture vials to produce a continuous saturating dose (0.5 mM). ⋯ Although no hexafluoroisopropanol-glucuronide was generated by slices from 4-, 6-, and 8-day-old neonates, by day 21, 17% of the total hexafluoroisopropanol is glucuronidated. This contrasts with the lower levels of free hexafluoroisopropanol typically seen in adults liver slices, wherein 51% of the hexafluoroisopropanol was glucuronidated. These studies indicate that sevoflurane is equally metabolized to hexafluoroisopropanol and F-, but a deficiency in glucuronosyltransferase occurs in neonates.
-
Drug Metab. Dispos. · Mar 1995
Comparative StudyComparative disposition of morphine-3-glucuronide during separate intravenous infusions of morphine and morphine-3-glucuronide in sheep. Importance of the kidney.
The disposition of morphine-3-glucuronide (M3G) in sheep was compared during separate constant infusions of morphine and M3G. Five ewes received a 15-min loading dose, followed by a constant infusion of morphine sulfate (10 mg/hr) or M3G (4 mg/hr for 4 sheep, 7.5 mg/hr for 1 sheep) for a further 5.75 hr. During the 5th-6th hr of infusion, blood was collected simultaneously from the aorta, pulmonary artery, hepatic vein, hepatic portal vein, renal vein, and posterior vena cava. ⋯ Regional net extraction ratios and total and regional clearances were calculated during the 5- to 6-hr period. After the infusions were ceased, there was prolonged elimination of M3G formed in situ from morphine compared to when infused as M3G. No morphine or M6G was detected in the plasma during and after infusion with M3G, nor were they found in urine collected up to 6 hr.(ABSTRACT TRUNCATED AT 250 WORDS)
-
Drug Metab. Dispos. · Mar 1994
Pharmacokinetics of tetraplatin administered intraperitoneally with reduced glutathione in mice.
Tetraplatin (Ormaplatin) has been developed as a second generation platinum complex because of its good antitumor activity against some cisplatin-resistant tumor cell lines. It is currently in clinical trials. Its reduction to diaminocyclohexane (DACH)-dichloroplatinum(II) [DACH-Pt(II)Cl2] or closely similar species is essential for binding to DNA to produce the desired antitumor effects. ⋯ Plasma and ascitic fluid from tumor-bearing mice demonstrated equivalent abilities to reduce tetraplatin rapidly. However, tetraplatin treatment of intraperitoneal-inoculated L1210/0 (parent) or L1210/DDP (cisplatin-resistant) tumor cells was unaffected by GSH. As GSH lowered systemic tetraplatin exposure in vivo without compromising antitumor activity against peritoneal tumor models, the combination of thiol and tetraplatin may be clinically useful in the treatment of intraperitoneal disseminated cancers.
-
Drug Metab. Dispos. · Nov 1993
Comparative StudyDisposition of morphine and its 3- and 6-glucuronide metabolites during morphine infusion in the sheep.
A sheep preparation was used to examine the regional formation and extraction of morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), relative to the regional extraction of morphine, at four morphine dose rates. On separate occasions, four ewes received a 15-min loading infusion of morphine sulfate, followed by a constant infusion at 2.5, 5, 10, or 20 mg/hr for an additional 5.75 hr. During the 5th to 6th hr of infusion, blood samples were collected simultaneously from the aorta, pulmonary artery, hepatic vein, hepatic portal and renal veins, posterior vena cava, and coronary and sagittal sinuses. ⋯ The mean lambda for morphine, M3G, and M6G was 1.25 +/- 0.17, 0.80 +/- 0.03, and 0.82 +/- 0.09, respectively. The mean total body clearance of morphine with respect to blood was 1.58 +/- 0.27 liters/min. Mean (+/-SD) percentage urinary recoveries as morphine, M3G, and M6G were 14.7 +/- 8.5, 75.4 +/- 11.1, and 0.49 +/- 0.39, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)