Single 25 mg intravenous and 50 mg oral doses of trazodone were given to 43 healthy subjects, divided into young men and women (aged 18 to 40 years) and elderly men and women (aged 60 to 76 years). Among men, trazodone volume of distribution (Varea) was increased in elderly vs. young subjects (1.15 vs. 0.89 L/kg; P less than 0.05), and clearance decreased (1.65 vs. 2.31 ml/min/kg; P less than 0.05), thereby increasing elimination half-life (t1/2) in elderly men (8.2 vs. 4.7 hours; P less than 0.001). Varea in women was also increased in the elderly (1.5 vs. 1.27 L/kg; P less than 0.02), causing increased t1/2 (7.6 vs. 5.9 hours; P less than 0.05), but clearance was unrelated to age. Absolute bioavailability of oral trazodone averaged 70% to 90% and was unrelated to age or sex. In 23 obese subjects (mean weight 112 kg) vs. 23 matched control subjects of normal weight (mean 65 kg), Varea was greatly increased (162 vs. 67 L; 1.43 vs. 1.04 L/kg; P less than 0.001) and was highly correlated with body weight (r = 0.91). Clearance was unchanged between groups (146 vs. 136 ml/min), but the increased Varea caused prolonged t1/2 in obese subjects (13.3 vs. 5.9 hours; P less than 0.001). Reduced clearance of trazodone among elderly men may indicate a need for dosage reduction during chronic therapy. In obese individuals, choice of dosage during chronic treatment should be based on ideal rather than total body weight.

Previous studies demonstrated that plasma clearance of organic anions such as bilirubin, bile acid, sulfobromophthalein (BSP) and indocyanine green (ICG), was reduced from 36% (bile acid) to 55% (ICG) in fasted (3 days) horses. It is believed that a general decline in carrier-mediated hepatic uptake may have accounted for those changes. However, fasting may also affect hepatic blood flow, thereby contributing to reduced clearance of these compounds. In order to test this hypothesis, plasma clearance of antipyrine, acetaminophen and lidocaine, drugs known to be cleared by the liver yet not suspected of undergoing carrier-mediated hepatic uptake, were investigated in nine healthy adult mares (three horses/drug group) before and following a 3-day fast. Results demonstrate that fasting decreased clearance of organic anions from previous studies more than clearance of drugs used in these studies. In addition, clearance of lidocaine, the drug with the highest plasma clearance and therefore the drug most likely to be affected by reduced hepatic blood flow, was affected least by fasting. Therefore, reductions in clearance of these compounds due to fasting must not be due entirely to reductions in hepatic blood flow, but must also involve reductions in intrinsic hepatic clearance.

No abstract

Ten healthy volunteers received a single 50-mg dose of diphenhydramine (DP) hydrochloride intravenously and orally on two separate occasions. Kinetics of DP and a major demethylated metabolite (DMDP) were determined from multiple plasma samples drawn during a 24- to 48-hour period after dosage. Modification of a gas chromatographic (GC) technique allowed simultaneous quantitation of DP and DMDP. Mean kinetic variables for DP after intravenous (IV) dosage were: volume of distribution, 4.5 L/kg; elimination half-life, 8.4 hours; clearance, 6.2 mL/min/kg. After oral DP administration, a peak plasma level of 66 ng/mL was reached 2.3 hours after dosage. Systemic availability was 72%, nearly identical to the predicted estimate (71%) based on clearance of IV DP relative to hepatic blood flow. Appearance of the metabolite, DMDP, mirrored disappearance of DP; the area under the plasma concentration-time curve (AUC) for DMDP was highly correlated (r = .79, P less than .05) with a clearance of IV DP. However, metabolite AUC was significantly higher after oral as opposed to IV DP (218 vs 145 hr-ng/mL, P less than .05). Because DP and DMDP elute nearly identically on standard GC systems, methodologic modifications are needed to resolve them. Coelution of the two compounds could bias kinetic data based on plasma concentration presumed to be specific for intact DP.

Thiopurine methyltransferase (TPMT), is an enzyme detected in the human red blood cell that catalyzes the S-methylation of thiopurine drugs and is known to exist as a genetic polymorphism in white subjects. Investigations in this laboratory of red blood cell TPMT showed interethnic differences also existed in North American black subjects. A sample group of black subjects in Florida had a mean activity of 8.64 +/- 3.47 U/ml red blood cells and an antimode of 6.5 units, which represented values significantly lower than those obtained for both the mean activity and the antimode in other populations. The findings of this study suggest the possibility that TPMT activity may be under genetic control in North American black subjects and that this ethnic group may be at greater risk of experiencing thiopurine-induced toxicity caused by the lower overall mean activity of the enzyme.

The effect of ciclosporin (CS) on hepatic and renal glutathione was investigated in 36 male Sprague-Dawley rats weighing 200–250 g each. CS (120 µg/kg/day, i.p.) treatment caused a significant decrease in both hepatic and renal glutathione content. The rat hepatic glutathione levels decreased by 16 % within 1 h of a single CS treatment and continued decreasing to 50% following chronic treatment with CS for 7 days. Renal glutathione content decreased only marginally (3%) within 1 h of CS treatment. However, it decreased by 17% within 24 h and continued to decrease during the 7 days of chronic treatment. This decrease in the content of both hepatic and renal glutathione may contribute to the toxicity observed during treatment with CS.

No abstract

Healthy volunteers received single doses of either phenytoin (300 mg IV), alprazolam (1 mg orally) or lorazepam (2 mg IV) on two occasions in random sequence. One of the two trials was a control; for the other trial, subjects ingested metronidazole, 250 mg three times daily beginning 4 days prior to and continuing for the duration of each kinetic study. Compared with control, metronidazole significantly prolonged phenytoin half-life (23 versus 16 hours, P less than .02) and reduced its clearance (.28 versus .33 mL/min/kg, P less than .005), known to depend on aromatic hydroxylation. However, metronidazole did not significantly alter kinetic variables for either alprazolam (metabolized by aliphatic hydroxylation) or lorazepam (metabolized by glucuronide conjugation). Thus, metronidazole has the capacity to impair the clearance of certain oxidatively metabolized drugs, but there is no apparent way to predict which drugs will be so influenced.