Transdermal application of lovastatin to rats causes profound increases in bone formation and plasma concentrations.

Introduction: Statins are drugs that inhibit HMG Co-A reductase and have been shown to enhance bone formation in vitro and in vivo in rodents. However, the statins currently used for cholesterol-lowering have been selected for their capacity to target the liver where their effects on cholesterol synthesis are mediated and they undergo first pass metabolism. When given in lipid-lowering doses, these agents do not likely reach sufficient blood concentrations to reliably cause substantial increases in bone formation in humans.

Effect of high-dose vitamin C on the steady-state pharmacokinetics of the protease inhibitor indinavir in healthy volunteers.

Study Objective: To determine whether daily high-dose vitamin C alters the steady-state pharmacokinetics of indinavir, a protease inhibitor indicated for treatment of the human immunodeficiency virus type 1.

Design: Prospective, open-label, longitudinal, two-period time series.

Setting: University medical center.

High-dose omeprazole: use of a multiple-dose study design to assess bioequivalence and accuracy of CYP2C19 phenotyping.

The objectives of this multiple-dose study were to compare the performance of a new formulation of omeprazole (40 mg) with that of an established formulation and to assess the accuracy of CYP2C19 phenotyping during high-dose chronic administration. Twenty-eight healthy subjects were randomized (1:1) to receive 40 mg of either Gasec-40 Gastrocaps (Mepha) or Antra 40 (Astra) daily for 5 days. The pharmacokinetics of omeprazole and the omeprazole/5'-hydroxyomeprazole ratio 3 hours postdose were assessed on day 5.

Glutathione S-transferase in human endometrium: quantitation and interindividual variability in isoform content.

Objectives: The goals of the present study were to determine whether human endometrium contains glutathione S-transferases (GSTs), to identify the isoforms present (if any) and to assess the causes of any intersubject variability which was observed.

Method: Hysterectomy patients (n = 32, 13 with endometrial carcinoma) were examined in the core study. The ability of cytosol from these endometria to conjugate 1-chloro-2,4-dinitrobenzene was measured.

Ampicillin vs. Penicillin for in utero therapy.

The pharmacokinetics of penicillin G and ampicillin are reviewed as they pertain to their potential use in in vitro therapy.

Accumulation kinetics of propranolol in the rat: comparison of Michaelis-Menten-mediated clearance and clearance changes consistent with the "altered enzyme hypothesis".

(+)-Propranolol was infused at two rates into the pyloric vein (a portal vein tributary) of 15 male Sprague Dawley rats until apparent steady-state conditions were established (i.e., 8 hr at each rate).

The hepatic first-pass metabolism of problematic drugs.

The first-pass hepatic metabolism of a number of important therapeutic agents is inconsistent with traditional models that assume that the hepatic extraction ratio of a drug is constant in each individual (independent of the concentration of drug in the hepatic sinusoidal blood and also independent of the history of exposure to the drug). In this review, the authors examine the first-pass metabolism of five "problematic drugs" (propranolol, lidocaine, propafenone, verapamil, and nitroglycerin). Each of these compounds has unique facets to its hepatic clearance and pharmacokinetics as well as striking similarities.

Pharmacokinetics of D-propranolol following oral, intra-arterial and intraportal administration: contrasting effects of oral glucose pretreatment.

Several research groups have reported that in man the oral administration of propranolol with food leads to a marked increase (about 50 per cent) in the area under the plasma concentration-time curve (AUCpo) of this well absorbed and highly metabolized drug. An acute change in hepatic metabolic enzyme activity has been postulated as one of the mechanisms which could be responsible for this observed 'food effect'. The administration of simple carbohydrates such as glucose and fructose has been documented to influence hepatic drug metabolism.

The influence of vitamin K3 treatment on the pharmacokinetics and metabolism of (+)-propranolol in the rat.

The effects of vitamin K3 treatment on the pharmacokinetics and metabolism of (+)-propranolol and the consequences of hepatic injury associated with vitamin K3 treatment were examined in groups of male Sprague-Dawley rats. When vitamin K3 (20 mg/kg) in polyethylene glycol 300 (PEG 300) was coinfused with (+)-propranolol (2 mg/kg) into the pyloric vein (a tributary flowing directly into the hepatic portal vein), a significant decrease in the intrinsic clearance of total drug (CLint) from 94.1 +/- 50.

Pharmacokinetic and metabolic aspects of the moclobemide-food interaction.

The effect of a protein-rich meal on the pharmacokinetics of moclobemide was studied after intravenous (75 mg) and oral (100 mg) administrations of this selective MAO-A inhibitor to eight healthy male volunteers. The meal chosen did not affect plasma concentration-time curves of the drug after oral administration apparently, because the influence of blood flow changes to the liver on hepatic first-pass metabolism (AUC increases) and on systemic clearance (AUC decreases) balance each other out.

Development of a bacteria-independent model of the multiple organ failure syndrome.

Criteria that allow definition of the multiple organ failure syndrome include pulmonary, hepatic, renal, and gut barrier dysfunction along with characteristic histopathologic changes. It has been difficult to study multiple organ failure due to lack of a satisfactory experimental model that would reproduce the pathophysiologic and histopathologic characteristics, would be stable enough to allow study over several days, and would be free of exogenous primary bacterial infection. We have studied pathophysiologic and histopathologic alterations in a potential model of multiple organ failure.

Lack of effect of treatment with human recombinant-tumour necrosis factor (HrTNF) on the binding of quinidine to alpha 1-acid glycoprotein (AGP).

Tumour necrosis factor (TNF) is known to be a key mediator in the acute phase response and its administration has been shown to cause a five fold increase in serum alpha 1-acid glycoprotein (AGP) concentration in the rat. Since, in man, plasma AGP level determines the protein binding of many important drugs (e.g.

Influence of posture on hepatic perfusion and the presystemic biotransformation of propranolol: simulation of the food effect.

Several research groups have reported that the oral administration of propranolol with protein-rich food leads to a marked increase (mean + 60%) in the area under the drug plasma concentration-time curve (AUC oral) of this highly metabolized and well-absorbed drug. It has been postulated that this "food effect" is caused at least in part by a transient increase in hepatic blood flow (QH) with its associated decrease in first-pass metabolism (hepatic extraction is a monotonic decreasing function of QH). A randomized crossover study using postural manipulations to produce changes in QH of the magnitude observed after food consumption (20% to 50%) was performed in an attempt to isolate the contribution of transient changes in QH to the food effect phenomenon.

Disopyramide pharmacokinetics and metabolism: effect of inducers.

1. The disposition of orally administered disopyramide was studied in a population of smokers (n = 6) and non-smokers (n = 8) before and during phenobarbitone treatment (100 mg daily for 21 days; Cp 21st day = 13.9 +/- 2.

Lack of effect of smoking on the metabolism and pharmacokinetics of quinidine in patients.

The urinary metabolite profile of quinidine and the oral clearance of this drug were studied under steady state conditions in five smoking and nine non-smoking patients. No significant differences were observed in the urinary recovery of unchanged quinidine, 3S-3-hydroxyquinidine, 2'-oxoquinidinone or quinidine-N-oxide between smokers and non-smokers. In addition, the plasma clearance of quinidine was not affected by the smoking status of subjects.

The pharmacokinetics of meperidine in acute trauma patients.

Traumatic injury has the potential to alter the hepatic clearance and hence the efficacy and toxicity of drugs by a variety of mechanisms. These include changes in hepatic microsomal enzyme activity, hepatic blood flow rate, and plasma protein binding. Unfortunately, there have been few pharmacokinetic studies in trauma patients.

Free drug concentration monitoring in clinical practice. Rationale and current status.

Recent advances in techniques to determine free drug concentrations have lead to a substantial increase in the monitoring of this parameter in clinical practice. The majority of drug binding to macromolecules in serum can be accounted for by association with albumin and alpha 1-acid glycoprotein. Albumin is the primary binding protein for acidic drugs, while binding to alpha 1-acid glycoprotein is more commonly observed with basic lipophilic agents.

Indocyanine green: pharmacokinetics in the rabbit and relevant studies of its stability and purity.

The plasma concentration-time profile of indocyanine green (1) in the rabbit was determined by spectrophotometric and high-performance liquid chromatographic (HPLC) analysis following doses of 5 or 25 mg/kg. Spectrophotometric analysis yielded plasma concentration estimates that were higher than those obtained by an HPLC method and this difference was particularly large at time points greater than or equal to 30 min postdose. Chromatograms of plasma samples from each rabbit exhibited two peaks, both of which were maximal in the first postdose sample, suggesting an impurity in the commercial preparation.

Applicability of capillary gas liquid chromatography to the measurement of free fraction of disopyramide in human plasma.

A sensitive and specific capillary gas liquid chromatographic nitrogen/phosphorus selective detection technique was used to measure unbound disopyramide in human plasma. The concentration dependent protein binding of disopyramide was examined. Various concentrations of disopyramide alone ranging from 0.

Effects of hydralazine, nitroglycerin, and food on estimated hepatic blood flow.

Several recent studies have shown that hydralazine and nitroglycerin may increase the apparent oral bioavailability of high-clearance drugs. It has been postulated that the mechanism responsible may be a vasodilator-induced transient increase in hepatic blood flow with an associated reduction in first-pass metabolism. To test this hypothesis, we examined the effect of hydralazine (25 mg) and sublingual nitroglycerin (2 doses of 0.

Estimation of tris(2-butoxyethyl) phosphate in biological fluids: novel intersubject variability in recovery from human serum.

Tris(2-butoxyethyl) phosphate (I), a plasticizer commonly found in evacuated blood collection tubes, displaces many basic drugs from their binding sites on serum proteins and causes them to redistribute from serum into red blood cells (i.e., artificially lowering serum or plasma drug concentration).