Robert A. Blouin

Endotoxin administration to humans inhibits hepatic cytochrome P450-mediated drug metabolism.

In experimental animals, injection of gram-negative endotoxin (LPS) decreases hepatic cytochrome P450-mediated drug metabolism. To evaluate this phenomenon in a human model of gram-negative sepsis, LPS was administered on two consecutive days to healthy male volunteers during which time a cocktail of antipyrine (AP-250 mg), hexobarbital (HB-500 mg), and theophylline (TH-150 mg) was ingested and the apparent oral clearance of each drug determined. Each subject had a control drug clearance study with saline injections. In the first experiment, six subjects received the drug cocktail 0.5 h after the first dose of LPS. In the second experiment, another six subjects received the drug cocktail 0.5 h after the second dose of LPS. In both experiments, LPS caused the expected physiologic responses of inflammation including fever with increases in serum concentrations of TNF alpha, IL-1 beta, IL-6, and acute phase reactants. In the first experiment, only minor decreases in clearances of the probe drugs were observed (7-12%). However in the second experiment, marked decreases in the clearances of AP (35, 95% CI 18-48%), HB (27, 95% CI 14-34%), and TH (22, 95% CI 12-32%) were seen. The decreases in AP clearance correlated with initial peak values of TNF alpha (r = 0.82) and IL-6 (r = 0.86). These data show that in humans the inflammatory response to even a very low dose of LPS significantly decreases hepatic cytochrome P450-mediated drug metabolism and this effect evolves over a 24-h period. It is likely that septic patients with much higher exposures to LPS have more profound inhibition of drug metabolism.

Vancomycin pharmacokinetics in normal and morbidly obese subjects.

In an uncontrolled study, vancomycin pharmacokinetics were determined in four normal (total body weight [TBW], 65.9 to 89.1 kg) and six morbidly obese (TBW, 111.4 to 226.4 kg) subjects. The morbidly obese subjects were investigated 3 to 4 h after gastric bypass surgery. Mean terminal half-lives, volumes of distribution, and total body clearances for the normal controls and the morbidly obese (TBW, 111.4 to 226.4 kg) subjects. The morbidly obese subjects were investigated 3 to 4 h after gastric bypass surgery. Mean terminal half-lives, volumes of distribution, and total body clearances for the normal controls and the morbidly obese subjects were 4.8 h, 0.39 liter/kg, and 1.085 ml/min per kg versus 3.2 h, 0.26 liter/kg TBW, and 1.112 ml/min per kg TBW. The mean terminal half-life and volume of distribution values were significantly different between the two groups. Strong correlations were found between TBW and both volume of distribution (correlation coefficient, 0.943) and total body clearance (correlation coefficient, 0.981). There results implied that TBW should be used to calculate vancomycin doses for morbidly obese patients. This was supported by the finding that there was no significant difference in the daily dose (in milligrams per kilogram per day) required to produce an average steady-state concentration of 15 micrograms/ml in the two groups (23.4 +/- 1.5 mg/kg per day for normal weight subjects and 24.0 +/- 3.4 mg/kg per day TBW for the postsurgery morbidly obese subjects). Therefore, the morbidly obese required higher total doses (in milligrams per day) than did normal weight subjects to achieve the same mean steady-state concentrations. In addition, normal weight and morbidly obese subjects had similar volumes of the central compartment (7.7 and 6.4 liters, respectively). To avoid high transient peak concentrations which would occur when obese patients are given larger total doses (in milligrams per day), maintenance doses may be given at more frequent intervals. The shorter mean terminal half-lives observed in morbidly obese patients allows more frequent dosing without excessive accumulation.

The cytochrome P450 2D6 (CYP2D6) enzyme polymorphism: Screening costs and influence on clinical outcomes in psychiatry

This study examined factors that affect cost, reliability, and the value of determining the cytochrome P450 2D6 (CYP2D6) polymorphism in clinical practice.

Clinical Pharmacokinetics of Verapamil

SummaryVerapamil is widely used in the treatment of supraventricular tachyarrhythmias as well as for hypertension and control of symptoms in angina pectoris. Unlike other calcium antagonists, detailed pharmacokinetic data are available for verapamil. Plasma concentrations of verapamil appear to correlate with both electrophysiological and haemodynamic activity after either intravenous or oral drug administration, although considerable intra- and intersubject variation has been found in the intensity of pharmacological effects resulting at specific plasma drug levels.Verapamil is widely distributed throughout body tissues; animal studies suggest that drug distribution to target organs and tissues is different with parenteral administration from that found after oral administration. The drug is eliminated by hepatic metabolism, with excretion of inactive products in the urine and/or faeces. An N-demethylated metabolite, norverapamil, has been shown to have a fraction of the vasodilator effect of the parent compound in in vitro studies.After intravenous administration, the systemic clearance of verapamil appears to approach liver blood flow. The high hepatic extraction results in low systemic bioavailability (20%) after oral drug administration. Multicompartmental kinetics are observed after single doses; accumulation occurs during multiple-dose oral administration with an associated decrease in apparent oral clearance. Norverapamil plasma concentrations approximate those of verapamil following single or multiple oral doses of the parent drug.Because of the complex pharmacokinetics associated with multiple-dose administration and the variation in individual patient responsiveness to the drug, ’standard’ dosing recommendations are difficult to determine; use of verapamil must be titrated to a clinical end-point. Further, the potential for alteration in verapamil’s disposition by the presence of hepatic dysfunction or cardiovascular disorders which result in altered hepatic blood flow is only now becoming apparent. A potentially toxic interaction has been reported between verapamil and digoxin, in which renal excretion of the glycoside is impaired, but the true clinical significance of this remains debatable. Combination therapy with verapamil and β-adrenoceptor blocking compounds has been advocated by some investigators, but may be hazardous because of the additive negative inotropic and chronotropic effects inherent in both agents.

Age and phenytoin kinetics in adult epileptics

Michaelis‐Menten parameters for rate of drug metabolism (Vmax) and the serum concentration at which metabolism is half of Vmax (Km) were determined in 92 adult epileptic patients taking phenytoin who were 21 to 78 yr old. The patients received no known inhibitors or inducers of phenytoin metabolism. Results of physical examinations and tests of liver function and total bilirubin and albumin concentration were normal. Divided into age groups, Vmax values were 7.5 ± 2.2, 6.6 ± 1.8, and 6.0 ± 1.9 mg/kg/day for the 20‐ to 39‐, 40‐ to 59‐, and 60‐ to 79‐yr‐old subjects, respectively. Values for those in the 60‐ to 79‐yr‐old group were substantially less than those for the youngest subjects (20‐ to 39‐yr‐olds; P < 0.05). Linear regression analysis indicated a decline in Vmax with age (r = −0.518). Km values did not appear to be influenced by age; means ranged from 5.4 to 5.8 µg/ml. As a result of these changes, the 60‐ to 79‐yr‐old group would require, on the average, 21% less phenytoin per day than the 20‐ to 39‐year‐olds to maintain a steady‐state concentration of 15 µg/ml. First doses can be based on these data and maintenance doses arrived at based on clinical response.

Pharmacokinetics of calcium-entry blockers

Effective use of drugs in therapy depends not only on clinical acumen but also on the availability of relevant pharmacokinetic and pharmacodynamic data. Such information assists in development of safe dosing regimens, prediction of abnormal handling of drugs in states of disease and disorder and anticipation of drug interactions. For the calcium-entry blocking agents now available in the United States (verapamil, nifedipine and diltiazem), these data appeared well after clinical patterns of use evolved. Nonetheless, their relevance continues to be demonstrated by the dependence of each agent on intact liver blood flow and function for normal rates of elimination; by the nonlinear kinetic characteristics for verapamil and diltiazem (and probably for nifedipine, as well) and the derivative implications for decreased dosing frequency requirements; and by observations now appearing on the relation between plasma drug levels and drug effects, both therapeutic and toxic. Such data are discussed herein, with emphasis on those aspects that impact on the clinical use of the calcium-entry antagonists.

Age‐associated stereoselective alterations in hexobarbital metabolism

This clinical investigation was designed to study the influence of age on stereoselective drug disposition using hexobarbital as a model marker. The disposition of hexobarbital enantiomers was investigated in 10 young and 10 elderly, healthy male volunteers. Mean oral clearance (±SD) of d‐hexobarbital (1.9 ± 0.5 vs. 1.7 ± 0.3 ml/min/kg; P > 0.05) did not differ significantly between the young and elderly subjects, respectively. However, despite wide intersubject variability, l‐hexobarbital mean oral clearance (± SD) was approximately twofold greater in the young than in the elderly subjects (16.9 ±11.9 vs. 8.2 ± 3.2 ml/min/kg; P < 0.05). This resulted in a significantly greater enantiomeric oral clearance ratio in the young when compared with the elderly subjects (8.3 ± 3.4 vs. 4.7 ± 1.4; P < 0.01). No significant difference (P > 0.05) in pharmacologic response after hexobarbital administration was found between the two groups. Demonstration of an age‐related preferential decline in metabolism of one enantiomer over another has not been reported previously for any racemic drug in animals or humans.

Tobramycin pharmacokinetics in morbidly obese patients

Tobramycin kinetics were examined in 9 morbidly obese women following a single intavenous (120 mg) bolus. After the injection, serum elimination conformed to a 2‐compartment open model with a and β t½s of 0.285 and 2.1 hr. The volume of distribution (Varea) was determined to be 0.44 l/kg ideal body weight (IBW) and 0.20 l/kg total body weight (TBW). To normalize Varea to 0.26 l/kg, 58% of the patients’ adipose weight (TBW — IBW) must also be taken into account.

Cytochrome P450 and antioxidant activity in interleukin-6 knockout mice after induction of the acute-phase response

Hepatic cytochrome P450 (CYP) expression and antioxidant activity have been shown to decrease following endotoxin (lipopolysaccharide [LPS]) or proinflammatory cytokine administration. Using mice deficient in interleukin-6 (IL-6), the role of IL-6 in the regulation of hepatic CYP activity, glutathione (GSH) metabolism, and catalase (CAT) activity was analyzed after LPS administration. Administration of LPS produced comparable decreases in hepatic CYP3A activity in WT B6x129 (WT) mice and IL-6 knockout mice. No decrease was observed for CYP2D9 activity after LPS administration in either WT or IL-6 knockout mice. LPS administration significantly increased hepatic and renal CYP2E1 and CYP4A activity in WT mice, with no effect in IL-6 knockout mice. CYP2A12 activity increased in IL-6 knockout, mice with no change in WT mice after LPS administration. LPS administration had no significant effect on hepatic GSH reductase, GST peroxidase, GSH-S-transferase (GST), or total GSH in either WT or IL-6 knockout. However, hepatic CAT activity was significantly reduced in WT mice after LPS administration, with no effect in IL-6 knockout mice. These results support IL-6 as a critical mediator of the effects of LPS on specific hepatic and renal CYP activities and hepatic CAT activity.

The Evaluation of Creatinine Clearance in Spinal Cord Injury Patients

The parameters of age, height, weight, serum creatinine and 24-hour urinary creatinine production were measured in 101 consecutive spinal cord injury patients (79 men and 22 women, 43 quadriplegics and 58 paraplegics) admitted to a rehabilitation hospital. Creatinine production was significantly lower than that of age and sex-matched hospitalized controls, upon whom commonly used nomograms for evaluation of endogenous creatinine clearance are based. Therefore, these nomograms grossly overestimate the creatinine clearance in paralyzed patients, which often results in aminoglycoside overdosage. Regression analysis identified the interval since injury and age as important determinants of creatinine production. We propose 2 simple equations and nomograms that should allow more accurate prediction of creatinine clearance in spinal cord injury patients.