Low Extraction Ratio Research Articles

Hepatic extraction of hexarelin, a new peptidic GH secretagogue, in the isolated perfused rat liver.

To assess the hepatic extraction of hexarelin (HEX), a novel peptidyl GH secretagogue, in the isolated perfused rat model and document the in vitro binding of HEX to plasma proteins using plasma from rats, dogs, pigs, and humans. Rat liver was perfused in situ using a recirculating system. The recirculating perfusate consisted of a Krebs Henseleit buffer containing 20% (v/v) prewashed bovine red blood cells, 1% albumin, and lg/L dextrose. Three HEX concentrations of 5, 50, and 500 ng/ml were examined. In vitro plasma binding was determined by the ultrafiltration method. The disappearance rate constant (K), half-life (t1/2), clearance (Cl), and hepatic extraction ratio (E) were: K = 0.013-0.014 min-1, t1/2 = 45-55 min, Cl = 0.345-0.401 ml/min/g liver, and E = 19-21% for the different concentrations of HEX. A linear increase in AUC (270-24334 min pmol/ml) was observed with increasing concentrations. Binding of HEX to plasma proteins of rats, dogs, pigs, and humans was 68.7 +/- 0.8%, 78.7 +/- 0.6%, 67.3 +/- 0.7%, and 65.2 +/- 0.6% respectively. Plasma binding was concentration-independent in the range between 0.003-3 microM for the four species examined. These results show that 1) the hepatic extraction of HEX is low, 2) the hepatic clearance is concentration independent up to 500 ng HEX/ml of perfusate, and 3) the plasma protein binding of HEX is significant over the dose range studied. HEX exhibits a low hepatic extraction ratio, allowing us to predict that its hepatic clearance may be limited upon HEX protein binding.

Serum protein binding of histamine H 1-antagonists. A comparative study on the serum protein binding of a sedating ([ 3H]mepyramine) and a non-sedating H 1-antagonist ([ 3H]loratadine)

Nowadays classical histamine H 1-receptor antagonists (antihistamines) are relatively rarely used in therapy against allergic disorders, mainly because they are able to penetrate the central nervous system (CNS) and induce subsequently unwanted side effects (most importantly sedation). In contrast, several modern H 1-antagonists have been claimed not to penetrate the CNS and lack the sedating properties. In this study, human serum protein binding, one of the properties which may influence brain penetration of H 1-antagonists, has been investigated by comparing the sedating H 1-antagonist [ 4H]mepyramine with the non-sedating H 1-antagonist [ 1H]loratadine. It is shown that human serum albumin (HSA) binding and total serum protein binding of [ 1H]mepyramine is low at therapeutic levels and at physiological pH (<30% bound) and strongly depends on the ionization state of this compound (p K d = 8.92). Our results demonstrate tha the unprotonated form of mepyramine in particular binds to serum proteins. This conclusion is supported by further results from plain HSA binding experiments, in this study, on six other unlabeled. ‘classical’ H 1-antagonists (i.e., diphenhydramine, chlorpheniramine, dimethindene, imipramine, azatadine, descarbocthoxyloratadine). On the other hand, the modern non-sedating H 1-antagonist loratadine (log P oct=4.40) binds to a high level to serum proteins at therapeutic levels (>95% bound). Our results further indicate that the main determinants of HSA binding for H 1-antagonists are lipophilicity and acid-base properties as expressed by log P and p K d, re (both included in the parameter log D oct). However, hydrogen bonding capacity ( Δlog P) is not correlated to serum protein bin series of H 1-antagonists investigated. We further propose that highly lipophilic non-sedating H 1-antagonists (i.e., loratadine, terfenadine, astemizole, temelastine) probably have a low extraction ratio in the brain due to the tight lipoid blood brain barrier and a relatively high extraction ratio in the porous peripheral tissues.

Dose-independent pharmacokinetics of the cardioprotective agent dexrazoxane in dogs.

A randomized, four-way cross-over design was used to assess the disposition of the cardioprotective agent, dexrazoxane, in four male beagle dogs following single I.V. administration of 10, 25, 50, and 100 mg kg-1 doses. Parent drug was quantified in plasma and urine with a validated high-pressure liquid chromatographic-electrochemical assay. A two-compartment open model adequately described the dexrazoxane plasma concentration versus time data. The terminal half-life ranged between 1.1 and 1.3 h and the apparent steady-state distribution volume was 0.67 L kg-1. The systemic clearance (CL) ranged from 10.3 to 11.5 mL min-1 kg-1, while estimates of renal clearance approximated the glomerular filtration rate (GFR approximately 3.2-4.9 mL min-1 kg-1). Over the dose range evaluated, CL was dose independent (ANOVA, p = 0.33), while concentration at the end of infusion (Cend) and the area under the concentration versus time curve (AUC) were directly proportional to the dose (r > 0.999). The blood cell to plasma partitioning ratio was approximately 0.517 and drug was essentially unbound to plasma proteins (fu approximately 0.95). Dexrazoxane appeared to be subject to low organ extraction, since the hepatic and renal drug extraction ratios were on the order of 0.228 +/- 0.054 and 0.184 +/- 0.024, respectively. These results suggest a relatively small drug distribution space (approximately equal to total-body water) and low tissue and plasma protein binding. In light of the low plasma protein binding and extraction ratio exhibited by dexrazoxane, metabolic capacity and renal function would appear to be the predominant variables affecting the CL of this drug. The constancy of the half-life, CL, and VSS with increasing dose indicates dose-independent disposition for dexrazoxane. Thus a linear increase in the systemic exposure can be predicted over this dose range.

Geochemical Estimates of Paleorecharge in the Pasco Basin: Evaluation of the Chloride Mass Balance Technique

The Pasco Basin in southeastern Washington State provides a unique hydrogeologic setting for evaluating the chloride mass balance technique for estimating recharge. This basin was affected by late Pleistocene catastrophic floods when glacial dams in western Montana and northern Idaho were breached. It is estimated that multiple Missoula floods occurred between ∼13,000 and 15,000 years B.P. and reached a high water elevation of ∼350 m. These floods removed accumulated chloride from the sediment profile, effectively resetting the chloride mass balance clock at the beginning of the Holocene. The rate of chloride accumulation qCl in the sediments was determined by two methods and compared. The first method measured qCl by dividing the calculated natural fallout of 36Cl by a measured ratio of 36Cl/Cl in the pore water, while the second method used the total mass of chloride in the profile divided by the length of time that atmospheric chloride had accumulated since the last flood. Although the two methods are based on different approaches, they showed close agreement. In laboratory studies the sediment to water ratio for chloride extraction was sensitive to the grain size of the sediments; low extraction ratios in silt loam sediments led to significant underestimation of pore water chloride concentration. Br/Cl ratios were useful for distinguishing nonatmospheric (e.g., rock) sources of chloride. Field studies showed little spatial variability in estimated recharge at a given site within the basin but showed significant topographic control on recharge rates in this semiarid environment. An extension of the conventional chloride mass balance model was used to evaluate chloride profiles under transient, time‐varying annual precipitation conditions. This model was inverted to determine the paleorecharge history for a given soil chloride profile, and the parameters of the root extraction model required to estimate paleoprecipitation

Pharmacokinetics of oxamniquine in rabbit and rat.

The pharmacokinetics of the schistosomicidal agent oxamniquine (6-hydroxmethyl-2-isopropylaminomethyl-7-nitro-1,2,3,4-tetra hydroquinoline) were studied in 8 (4 male, 4 female) New Zealand White rabbits and 5 female Wistar rats, following intravenous administration (15 mg/kg). The pharmacokinetic parameters (mean +/- SD) in the rabbit and rat, respectively, were as follows: plasma clearance, 65.5 +/- 33 and 17.2 +/- 5.7 ml/min/kg; steady-state volume of distribution, 7.9 +/- 4.5 and 2.1 +/- 0.5 l/kg; terminal elimination half-life, 1.8 +/- 0.3 and 1.8 +/- 0.9 h. Oxamniquine appeared to be widely distributed in both species, although significantly higher in the rabbit. Similarly, plasma clearance was significantly higher in the rabbit. Using reported estimates of liver blood flow and fractions excreted unchanged in urine of the rabbit and rat, calculations based on blood clearances indicated that oxamniquine has a low hepatic extraction ratio (0.2) in the rat and an intermediate hepatic extraction ratio (0.6) in the rabbit. From separate experiments, however, hepatic extraction appeared to be low in the rabbit, suggesting that oxamniquine disposition is probably broadly similar in both rabbit and rat.

Pharmacokinetics and hepatic first‐pass effect of (−)‐carbovir in the anesthetized rat

Studies were designed to allow an in vivo estimation of the hepatic extraction ratio and to test the hypothesis that the pharmacokinetic parameters of (-)-CBV are significantly different during anesthesia. (-)-CBV was administered as an i.v. bolus followed by i.v. infusion into either the portal (n = 3) or the jugular (n = 3) veins of anesthetized male Sprague-Dawley rats. These studies indicate that (-)-CBV had a very low hepatic extraction ratio, in agreement with previous (-)-CBV in situ liver perfusion studies. Additionally, anesthesia was shown to alter the pharmacokinetics of (-)-CBV by reducing the total body clearance of this drug.

Hyaluronan in sepsis

Abstract: Sepsis and septic shock are important causes of morbidity and mortality in the intensive care unit (ICU). Mortality rates in septic shock are estimated to be 40‐5O%, in spite of modrn intensivc care. Death is commonly caused by cardiovascular collapse and multiple organ dysfunction syndrome (MODS). Hepatic dysfunction is a common component of MODS. and can have a major impact on prognosis and survival. Sepsis is, among other derangements, also accompanied by disturbed tissue water homeostasis with increased extravasation of water resulting in tissue oedema.Hyaluronan is an interstitial macromolecule that participates in the regulation of tissue hydration. It is normally present in small concentrations in the blood, and is rapidly cleared from the blood by the liver endothelial cells. The synthesis of hyaluronan can be stimulated by inflammatory mediators. Thus sepsis and hyaluronan turnover could interact in many ways. The aim of the present investigations was to study possible changes in circulating hyaluronan concentrations in relation to sepsis and septic shock.Plasma levels of hyaluronan were studied in 44 patients with infections and septic shock. Increased plasma concentrations were found, and the increase correlated to disease severity and outcome. In experimentally induced sepsis in pigs, an increase in circulating concentrations was found, and a relation to haemodynamic instability and outcome was seen. A moderate increase in blood hyaluronan concentrations was seen after surgical trauma in both humans and pigs. Crystalloid infusion therapy also caused a small increase in plasma hyaluronan concentrations in healthy volunteers, probably through an increased washout of interstitital hyaluronan. The hepatic turnover of hyaluronan was studied in septic shock patients. Low extraction ratios at high circulating concentrations were found, suggesting a reduced capacity of hepatic uptake and an increased inflow to the circulation. The kinetics of plasma turnover of hyalurorian were studied in septic and non‐septic ICU patients. A prolonged half‐life was seen among the septic patients, suggesting a reduced clearance capacity.In conclusion, sepsis is accompanied by increased circulating hyaluronan concentrations. The magnitude of thc increase seems to correlate to disease severity and outcome. The cause of this increase is suggested to be both reduced hepatic uptake function, and increased input to the circulation. The relative contribution of these mechanisms, and the possible clinical utility of plasma hyaluronan measurements, remain to be determined.

The oxygen consumption/oxygen delivery curve in severe preeclampsia: Evidence for a fixed oxygen extraction state

Increased total body oxygen consumption requirements are usually met by increased oxygen delivery and increased oxygen extraction. In certain conditions (e.g., adult respiratory distress syndrome) the ability to increase oxygen extraction is lost, and any increase in oxygen consumption depends on increased oxygen delivery. The objective of this study was to investigate the oxygen delivery/oxygen consumption relationship in severe preeclampsia. Thirty-two patients with severe preeclampsia (blood pressure > 160/110 mm Hg; 3 to 4+ proteinuria) were monitored with a pulmonary artery catheter. Baseline oxygen consumption and delivery in a group without volume expansion or pharmacologic vasodilatation were compared with those in a group who had received a magnesium sulfate infusion. Oxygen consumption, oxygen delivery, arterial-venous-oxygen difference, and the oxygen extraction ratio were low when compared to that for normal 32 to 38 week pregnancy. The oxygen extraction ratio, defined as the ratio of oxygen consumption to oxygen delivery, was abnormally low for pregnancy, especially considering the low oxygen delivery levels in these patients. Oxygen consumption was dependent on oxygen delivery over the entire range of values seen. Severe preeclampsia is associated with an abnormality of tissue oxygen extraction, as evidenced by a low and unresponsive oxygen extraction ratio. Oxygen consumption increases proportionately with increases in oxygen delivery without reaching an oxygen delivery-independent state. Even at high oxygen delivery levels the oxygen consumption in preeclamptic patients is still abnormally low for pregnancy.

The pharmacokinetic profile of nimesulide in healthy volunteers.

After oral administration of nimesulide 100mg in tablet, granule or suspension to healthy volunteers, the drug was rapidly and extensively absorbed. Mean peak plasma concentrations of 2.86 to 4.58 mg/L were achieved within 1.22 to 3.83 hours of administration. The presence of food did not reduce either the rate or the extent of nimesulide absorption. When administered in suppository form, nimesulide peak plasma concentrations were lower and occurred later than those achieved after oral administration; the bioavailability of nimesulide given by suppository ranged from 54 to 96%, relative to that of orally administered formulations. Nimesulide is rapidly distributed, principally throughout the extracellular fluid compartment; values for volume of distribution ranged from 0.19 to 0.39 L/kg. Nimesulide is extensively bound to plasma proteins: at concentrations ranging from 0.5 to 10 mg/L, the unbound fraction varied between 0.7 and 4.0%. With oral administration, nimesulide concentrations decline monoexponentially following peak levels. The estimated mean terminal half-life for nimesulide varied from 1.96 to 4.73 hours. Excretion of unchanged drug in urine and faeces is negligible. Nimesulide is mainly eliminated by metabolic transformation and the principal metabolite is the 4'-hydroxy derivative. The presence of other metabolites is being evaluated. Excretion of nimesulide metabolites in the urine and faeces accounts for about 80 and 20% of the administered dose, respectively. Total plasma clearance of nimesulide was 39.7 to 90.9 ml/h/kg, reflecting almost exclusive metabolic clearance. The drug has a low extraction ratio, close to 0.1. Differences in gender have only a limited influence on the pharmacokinetic profile of nimesulide and its hydroxylated metabolite. With twice-daily administration of nimesulide 100 mg (tablets) or 200mg (suppositories), steady-state is achieved within 24 to 36 hours (2 to 3 administrations). With oral nimesulide 100mg twice daily, only modest accumulation of nimesulide and its 4'-hydroxy derivative occurs (Rmin, 1.59 for nimesulide and 1.46 for the hydroxylated metabolite).

The allometric approach for interspecies scaling of pharmacokinetic parameters

A long standing problem in pharmacokinetics and toxicology is the extrapolation and correlation between results obtained in different animal species and man. Animal data may be scaled-up to predict PPs in man using the allometric approach. The allometric approach is empirical, but easy, and is based on the fact that the underlying physiological processes such as blood flow, heartbeat duration, breath duration etc. are essentially physical and related to B. This approach is generally applicable to compounds that are essentially renally excreted. For substances that are highly extracted by the liver, Cl tot is a function of the LBF among various species. Based on the concept of neoteny, use of brain weight affords a more correct approach to the scaling of Cl int of low extraction ratio drugs. By using the invariant pharmacokinetic time, the superficial differences in concentration-time profiles due to chronological time among different species are removed. Finally, as Boxenbaum (1984) has said “parameters to be scaled, independent variables, and the mathematical relationships used in the scaling process are all at the discretion of the investigator. There are no proper or improper approaches; the only limitations are those imposed by the investigator.”

Technetium-99m ( 99mTc) mercaptoacetyltriglycine: Update on the new 99mTc renal tubular function agent

Technetium-99m (99mTc) mercaptoacetyltriglycine (MAG3) is a new renal radiopharmaceutical that was recently introduced as a 99mTc-labeled replacement for iodine-131 (131I) o-iodohippurate (OIH). Since its introduction, a wide variety of in vitro and in vivo studies have been performed to characterize the high-performance liquid chromatography (HPLC)-purified complex and kit formulations. [99mTc]MAG3 has a slower plasma clearance, a higher plasma protein binding, less red blood cell (RBC) penetration, a lower extraction ratio, and a smaller volume of distribution than OIH. Because of the slower plasma clearance, [99mTc] MAG3 cannot be used as a direct measurement of effective renal plasma flow. Simplified methods have been developed to calculate [99mTc]MAG3 clearances, as well as regression equations to convert these clearances to an equivalent OIH value. The image quality of [99mTc]MAG3 is superior to [131I]OIH; the renogram curves and the fraction of the dose of the two agents that appears in the urine are almost identical, even though the plasma clearance of [99mTc]MAG3 is only 50% to 65% that of OIH. [99mTc]MAG3 compares favorably with OIH in patients with a wide range of clinical problems. The radiation dose to a patient with normal renal function using standard imaging doses is higher for [99mTc]MAG3 than for [131I]OIH, but in patients with impaired renal function, the radiation dose from [131I]OIH is much higher than [99mTc]MAG3. [99mTc]MAG3 also provides superior image quality compared with [99mTc]diethylenetriaminepentaacetic acid (DTPA) in patients with impaired renal function, but it is important to note that [99mTc]MAG3 cannot be used to measure the glomerular filtration rate (GFR). [99mTc]MAG3 is the most promising 99mTc tubular function agent to date, and it has replaced OIH and [99mTc]DPTA in a number of institutions. However, there are physiologic differences between these three agents and, therefore, they should not be expected to behave identically in all clinical conditions.

The Effect of Respiratory Disorders on Clinical Pharmacokinetic Variables

Respiratory disorders induce several pathophysiological changes involving gas exchange and acid-base balance, regional haemodynamics, and alterations of the alveolocapillary membrane. The consequences for the absorption, distribution and elimination of drugs are evaluated. Drug absorption after inhalation is not significantly impaired in patients. With drugs administered by this route, an average of 10% of the dose reaches the lungs. It is not completely clear whether changes in pulmonary endothelium in respiratory failure enhance lung absorption. The effects of changes in blood pH on plasma protein binding and volume of distribution are discussed, but relevant data are not available to explain the distribution changes observed in acutely ill patients. Lung diffusion of some antimicrobial agents is enhanced in patients with pulmonary infections. Decreased cardiac output and hepatic blood flow in patients under mechanical ventilation cause an increase in the plasma concentration of drugs with a high hepatic extraction ratio, such as lidocaine (lignocaine). On a theoretical basis, hypoxia should lead to decreased biotransformation of drugs with a low hepatic extraction ratio, but in vivo data with phenazone (antipyrine) or theophylline are conflicting. The effects of disease on the lung clearance of drugs are discussed but clinically relevant data are lacking. The pharmacokinetics of drugs in patients with asthma or chronic obstructive pulmonary disease are reviewed. Stable asthma and chronic obstructive pulmonary disease do not appear to affect the disposition of theophylline or beta 2-agonists such as salbutamol (albuterol) or terbutaline. Important variations in theophylline pharmacokinetics have been reported in critically ill patients, the causes of which are more likely to be linked to the poor condition of the patients than to a direct effect of hypoxia or hypercapnia. Little is known regarding the pharmacokinetics of cromoglycate, ipratropium, corticoids or antimicrobial agents in pulmonary disease. In patients under mechanical ventilation, the half-life of midazolam, a new benzodiazepine used as a sedative, has been found to be lengthened but the underlying mechanism is not well understood. Pulmonary absorption of pentamidine was found to be increased in patients under mechanical ventilation. Pharmacokinetic impairment does occur in patients with severe pulmonary disease but more work is needed to understand the exact mechanisms and to propose proper dosage regimens.

Increased hepatic nicotine elimination after phenobarbital induction in the conscious rat

Elimination parameters of [ 14C]nicotine in conscious rats receiving nicotine (0.3 mg/kg) either intravenously or orally were studied. The oral availability of unchanged nicotine, derived by comparison of the respective areas under the concentration vs time curves (AUC), was 89%, indicating low hepatic extraction ratios of about 10%. Pretreatment of rats with phenobarbital (PB) markedly increased hepatic first-pass extraction of nicotine. The oral availability of unchanged nicotine in plasma dropped to 1.4% of the corresponding values obtained from PB-treated rats receiving nicotine iv. After PB pretreatment, the clearance of iv nicotine was increased approximately twofold over controls, much less than the observed more than ninefold increase of hepatic first-pass extraction. It is assumed that extrahepatic metabolism contributed significantly to the rapid removal of nicotine from the plasma. The elimination of cotinine, originating from nicotine administered either po or iv, was significantly increased by PB pretreatment, as determined by the ratio of corresponding AUCs. The pattern of nicotine metabolites in urine also indicated an increase in the rate of cotinine metabolic turnover. The amount of norcotinine in the organic extract of urine paralleled PB microsomal enzyme induction. The ratio between urinary concentrations of the normetabolite and cotinine correlated strongly with the PB-induced state of rat liver. This may be a suitable indicator of PB-inducible hepatic cytochrome P450 isoenzyme(s). Since smoking habits in man are feedback-regulated by nicotine plasma concentrations, a similar increase of nicotine elimination by microsomal enzyme induction in man may be of relevance for tobacco consumption.

Effect of hypophysectomy on caffeine elimination in rats

Two groups of 8-week-old Sprague-Dawley male rats were used: 8 hypophysectomized (H[-]), operated on day 0, treated by daily sc tetracosactid (ACTHs: 10 micrograms), and thyroxine (T4:5 micrograms/100 g); 7 sham-operated, treated by sc saline solution. ACTHs, T4, saline solution were administered on days 7-16. The animals received po caffeine (CAF) 4 mg/kg as citrate salt on day 15. Ten blood samples were drawn from the tail. Plasma CAF concentrations were determined by HPLC. CAF apparent clearance and apparent volume of distribution were lower in H(-) rats than in controls: 0.281 +/- 0.072 vs 0.455 +/- 0.165 l/kg/h (-38%; P less than 0.05) and 0.520 +/- 0.239 vs 1.28 +/- 0.266 l/kg (-59%; P less than 0.01) respectively. CAF half-life was lower in H(-) rats than in controls: 1.33 +/- 0.621 vs 2.12 +/- 0.676 h (-37%; P less than 0.01). CAF is a drug with a low hepatic extraction ratio and low plasma protein binding. CAF clearance is therefore primarily dependent on intrinsic clearance, which depends on the activity of the enzymes involved in CAF metabolism. These data suggest that hepatic CAF metabolism is reduced in H(-) rats treated by SC ACTHs and T4. The decrease in CAF apparent volume of distribution is probably related to dehydration, as suggested by increase in urine flow and hematocrit. The CAF half-life was probably low because the volume of distribution was proportionally more decreased than the clearance. Our results suggest that the pituitary gland plays a role in the regulation of hepatic CAF metabolizing enzymes.

High-fat meals increase the clearance of cyclosporine.

High-fat meals increase the clearance and volume of distribution, but not the mean residence time, of cyclosporine in seven healthy volunteers when either plasma or blood analyses are used. This unexpected finding for a low-extraction ratio drug should not be explainable in terms of increased blood flow. We hypothesize that dietary fat can act as a carrier for cyclosporine and enhance both its volume of distribution and its clearance. We suggest that clearance then occurs following metabolism of lipids due to lipase activity within the hepatocyte, thereby releasing free drug for metabolism.

Hepatic extraction, metabolism and biliary excretion of doxorubicin in the isolated perfused rat liver.

The hepatic extraction, metabolism, and biliary excretion of doxorubicin (DX) were studied in the isolated perfused rat liver. Three doses of DX equivalent to 2, 20, and 100 mg/kg in rats were studied over a period of 3 h after bolus injection into the reservoir. DX and metabolites concentration in perfusate, bile, and liver were determined by high-pressure liquid chromatography. The hepatic extraction ratio was low (less than 0.24) and decreased progressively over the 3 h. The hepatic extraction and clearance were significantly lower at the highest dose. Doxorubicinol (DX-OL) was the only metabolite detected in the perfusate, accounting for less than 4% of the total AUC. Thirty-one to thirty-three percent of the dose was excreted into bile over 3 h as unchanged DX. This was reduced to 22% at the highest dose. Only 0.35%-1.33% of the dose was excreted as DX-OL. DX aglycones were found only in the liver, where they represented 20%-30% of the total fluorescence at 3 h. In conclusion, in this model DX has a low extraction ratio, is poorly metabolized and extensively excreted into bile.

Gamma camera renography with 99Tcm-MDP and 131I-Hippuran.

Nineteen patients with urologic disorders referred to bone scintigraphy were evaluated with a dual radioisotope technique using simultaneous injection of 99Tcm-MDP and 131I-Hippuran. The MDP and Hippuran renograms showed in general the same pattern and there was no difference between the kidney function determined with the two radionuclides. The peak of the MDP curves occurred later and was less distinct than that of the Hippuran curves. The residual activity of the kidneys 20 min after the injection was higher on the MDP renograms compared with the Hippuran renograms. The early sequential MDP images were superior in quality to the Hippuran images and to the renal images obtained at bone scintigraphy. The early MDP images correlated well with the findings at urography performed in 12 patients, as all cases of radiologically diagnosed hydronephrosis, reduction of renal parenchyma and renal mass lesions became demonstrated. Renal calculi were only diagnosed at urography. In conclusion, MDP cannot replace Hippuran as a renal radionuclide agent, mainly due to its lower extraction ratio and the high bone uptake. However, an increased use of early dynamic renal imaging is recommended in urologic patients referred to bone scintigraphy as valuable information about renal function may be obtained by this procedure.

Endogenous pancreatic polypeptide in different vascular beds: Relationship to release and degradation in subjects with normal and decreased kidney function

The plasma concentration of pancreatic polypeptide (PP-like immunoreactivity) was measured in different vascular beds in order to determine regional kinetics of endogenous PP in fasting, supine subjects with normal or moderately decreased kidney function. Patients with kidney disease (n = 10) had a significantly higher level of circulating PP than controls (n = 10): median PP = 52 (range 21 to 352) v 20 (6 to 143) pmol/L, respectively ( P < 0.02). Circulating PP was inversely correlated to 51Cr-EDTA plasma clearance ( r = −0.57, P < 0.02, n = 14) and directly correlated to serum creatinine concentration ( r = 0.70, P < 0.01). Hepatic venous PP was significantly higher than systemic PP in both controls and patients with kidney disease ( P < 0.001, n = 15). The values were positively correlated ( r = 0.98, P < 0.001; slope = 1.37 ±0.05, P < 0.001), indicating a progressively increasing rate of PP secretion in subjects with raised circulating PP. No statistically significant difference could be detected between systemic and renal venous PP or across the lung, left adrenal gland, or lower limb. Assuming steady state between secretion and biodegradation, the metabolic clearance rate of the peptide was estimated to be approximately 600 to 800 mL/min in controls and slightly below this value in patients with nephropathy. These results suggest that the raised circulating PP found in patients with decreased kidney function is due to both increased secretion and decreased degradation. We were unable to identify a single vascular bed as the place of elimination; more likely the biodegradation of circulating PP takes place in mary organs by a process involving a low plasma extraction ratio.

Influence of hypothermia on the pharmacokinetics of gentamicin and theophylline in piglets.

The influence of hypothermia on gentamicin and theophylline pharmacokinetics was studied in anesthetized pigs given an iv bolus of gentamicin and theophylline during normothermia (37 degrees C) and again 1 wk later after the induction of controlled hypothermia (29 degrees C). During hypothermia, the elimination half-time for gentamicin was significantly prolonged (135 +/- 19 min at 37 degrees C vs. 187 +/- 7 min at 29 degrees C), and there were significant decreases in the volume of the central compartment (Vc) of gentamicin, the gentamicin volume of distribution (Vd), and the gentamicin total body clearance (TBC). Hypothermia was associated with a small but significant decrease in theophylline Vd and Vc, but no change in TBC. In separate experiments, cardiac output decreased during the induction of hypothermia in a temperature-dependent fashion. The changes in gentamicin Vd and TBC may be explained by the decrease in cardiac output and the associated decrease in glomerular filtration rate. This study suggests that the elimination of theophylline, which has a relatively low hepatic extraction ratio, is not influenced by the hypothermia-induced decrease in liver blood flow.

Effects of ethanol on drug and metabolite pharmacokinetics.

Pharmacokinetic interactions of ethanol with other drugs, including its effects upon drug metabolite disposition, are reviewed in terms of clearance concepts. This approach is particularly useful in understanding the mechanisms of ethanol-drug interactions, i.e. in separating the effects of ethanol upon drug clearance, volume of distribution and plasma protein binding. The application of clearance concepts provides the basis for understanding the qualitative differences in ethanol interactions with low and high hepatic extraction ratio drugs. The effects of short and long term ethanol consumption upon different types of drug metabolism (oxidative, acetylation and glucuronidation) have been considered. Long term ethanol consumption may increase the clearance of a drug by induction of oxidative metabolism whereas short term consumption may decrease the clearance of such a drug. Clearance by N-acetylation appears to be increased in the presence of ethanol, and clearance by conjugation to glucuronic acid is decreased for some drugs by single-dose consumption of ethanol.