Differences In Volume Of Distribution Research Articles

Pharmacokinetic disposition of quinolones in human body fluids and tissues.

The unique pharmacokinetic properties as well as the body fluid and tissue penetration of quinolones are discussed. Quinolones are well absorbed from the gastrointestinal tract and are eliminated with considerable differences in their terminal half-lives. The major elimination pathways of quinolones are renal excretion and hepatic metabolism. Renally, these drugs undergo the potential excretion mechanisms (glomerular filtration, tubular secretion, reabsorption). In the liver, they are metabolised primarily by oxidation as well as by conjugative pathways. However, the metabolic pattern and extent of metabolism differ significantly between individual agents. Alterations in the pharmacokinetic disposition of these agents in liver and renal failure as well as in elderly patients are observed as predicted from their excretion pattern. In addition, quinolones can interact with a number of other compounds at hepatic (e.g. with xanthine derivatives), renal (with probenecid) and gastrointestinal (with antacids) sites. The volume of distribution of quinolones is considerably higher than body volume, which suggests intracellular penetration. Studies on tissue penetration show that concentrations exceeding plasma levels are obtained in most tissues. The highest tissue/plasma concentration ratios are achieved in lung and kidney, whereas concentrations in fat are considerably lower than in plasma. Body fluid penetration is introduced as a new approach to evaluate distribution kinetics of quinolones. With the exception of those in nasal secretions and ejaculate, body fluid levels of these drugs rarely reach plasma levels. The body fluid penetration model allows for differentiation among individual agents. There is no apparent relationship between differences in body fluid penetration of quinolones and differences in volume of distribution. For the clinical use of these drugs it is important that the concentrations achieved in body fluids and tissues are sufficient to kill most pathogens. A discussion on the relationship between plasma and tissue levels and the MICs of quinolones is, however, beyond the scope of this article.

Determination of beta-endorphins in alcoholic patients in the acute stage of intoxications: Relation with naloxone therapy: (Barret, L., F. Bourhis, H. Buffet, V. Danel and J. L. Debru. Drug Alcohol Depend19: 71–78, 1987.)

The number of trials looking at the gender effecton anesthetic agents is very limited. What evidence exists is not clear, but the general pattern suggests a difference in pharmacokinetics and pharmacodynamics between men and women for certain drugs. These differences may not be predictable within the same group of drugs, such as benzodiazepines; the gender effect may vary and sometimes may be completely opposite. Important gender factors, such as menopause, pregnancy, and use of oral contraceptives, may affect the pharmacokinetics and dynamics of drugs significantly. Difference in body weight and composition alone result in significant pharmacokinetic differences in volume of distribution, initial plasma concentration, organ blood flow, rate of redistribution, and rate of filtration by the kidney. The intrinsic activity of the cytochrome system appears to be affected by gender: The activity of CYP3A4 is 1.4 times greater in women than men, with the resultant increased metabolism of certain drugs in women. One possible explanation for this increased intrinsic activity in women may be the interaction of the sex steroids with the cytochrome systems. Increased sensitivity to drugs may result from interaction of the sex steroids with receptors such as the μ-opioid receptors. The sex hormones may affect other intrinsic substances such as beta-endorphins. For example, beta-endorphin levels are increase in pregnancy and along with progesterone are thought to result in the decreased MAC associated with pregnancy. Clearly, further studies are needed to identify which drugs are affected by gender as well as the causes for these differences. Last, how big these differences are and to what degree they are clinically significant must be determined.

Decreased hepatic elimination of pyrimethamine during malaria infection: Studies in the isolated perfused rat liver

The elimination of the antimalarial drug pyrimethamine was studied in isolated liver preparations from young rats (80–100 g) infected with merozoites of Plasmodium berghei two weeks earlier. Perfusate half-life of pyrimethamine was increased in livers from M.I. rats ( t 1/2 βcontrol group= 56 ± 11min vs M.I. group= 101 ± 12,P< 0.01), reflecting a decrease in hepatic clearance (3.6 ± 1.1ml/min vs 1.9 ± 0.5ml/min, P< 0.01). There was no significant difference in volume of distribution between livers from M.I. and control groups. Intrahepatic concentration of unchanged drug at 3 hr was 4–5-fold greater in livers from infected rats (control group= 4725 ± 2287ng/ml vs M.I. group= 22,324 ± 6824ng/ml), while liver: perfusate concentration ratios were not significantly different (control group= 30.8 ± 24.1 vs. M.I. group= 35.6 ± 20.3). We conclude that the hepatic elimination of pyrimethamine is substantially impaired in the malaria-infected rat.

Responses to intravenous and oral diltiazem in elderly and younger patients with systemic hypertension

Diltiazem concentrations and blood pressure, heart rate, PR interval and forearm vascular resistance responses to intravenous (25 and 50 mg) and oral (120 mg) diltiazem were compared in 13 elderly persons (mean age 68 ± 4 years) and 10 young persons (mean 30 ± 5 years) with essential hypertension. Diltiazem elimination was slower in the elderly. After a dose of 25 mg, clearance was 13 ± 4 ml/min/kg in the elderly and 23 ± 7 in the young (p < 0.05); after 50 mg, 16 ± 6 and 21 ± 12 ml/ min/kg (p < 0.05); and after oral administration, 22 ± 9 and 35 ± 14 ml/kg/min (p < 0.02). No age-related differences in volume of distribution (by model or area methods) were seen. Elimination half-lives were 4.5 ± 2.2 hours in the elderly and 3.8 ± 0.7 hour in the young persons (p < 0.01); 4.5 ± 1.6 and 3.3 ± 0.7 hours (p = 0.10); and 4.7 ± 1.5 and 3.3 ± 1.8 hours (p = 0.08) after 50, 25 and 120 mg. Maximal decreases in mean blood pressure were from 113 ± 14 to 91 ± 12 mm Hg (19%) in the elderly patients and from 108 ± 8 to 99 ± 9 mm Hg in the younger patients (8%) after 50 mg; from 106 ± 13 to 93 ± 14 mm Hg and from 109 ± 11 to 99 ± 13 mm Hg, respectively, after 25 mg; and from 113 ± 10 to 97 ± 10 mm Hg and from 109 ± 11 to 97 ± 8 after 120 mg orally. Heart rate increased transiently in only the young persons at the end of 50-mg infusions (from 77 ± 14 to 84 ± 8 beats/min, p < 0.05). After oral administration, heart rate decreased significantly in only the elderly (from 75 ± 10 to 65 ± 11 beats/ min at 3 hours after dosing, p < 0.01). Diltiazem (50 mg) produced third-degree heart block in 2 young. No second- or third-degree block occurred in the elderly. After 25-mg infusions, PR interval increased from 170 ± 22 to 219 ± 42 ms in the elderly (p < 0.01) and from 161 ± 12 to 214 ± 29 ms (p < 0.01) in the young patients. After 120 mg, peak increases were from 163 ± 21 to 183 ± 26 ms (p < 0.01) and from 164 ± 24 to 197 ± 27 ms (p < 0.01), respectively. Forearm vascular resistance changed significantly in only the elderly after 25 and 50 mg (from 11.2 ± 3.6 to 10 ± 3.5 U and from 16.6 ± 14 to 13.4 ± 9.5 U, respectively). In summary, slower clearance of diltiazem was found in elderly than in younger hypertensive persons, as were greater hypotensive effects. Reflex heart rate increases were seen in the younger patients and decreases in the elderly. PR prolongation was greater in the younger hypertensive persons.

Increased susceptibility to liver disease in relation to alcohol consumption in women.

Sex-related differences were prospectively studied in patients with the first presentation of alcoholic liver disease. Among 42 patients the diagnosis was cirrhosis in 8 women and 15 men, alcoholic hepatitis in 4 women and 1 man, steatosis in 6 women and 6 men, and no histologic changes were found in the liver biopsy specimens from 2 men (p greater than 0.1). The median (range) antipyrine clearance was 14.6 (1.0-64) versus 17.2 (3.0-83) ml/min and the clinical score in accordance with the Pugh modification of the Child-Turcotte classification was 8 (5-13) versus 8 (5-11) in the women and men, respectively (p greater than 0.05). In 5 women and only 1 man the antipyrine clearance was less than 5 ml/min, indicating an almost total loss of functional liver mass (p less than 0.05), whereas the Pugh score was above 11 in 6 women, but not in any of the men (p less than 0.05). On an average, the men estimated their total lifetime consumption of alcohol to be 2.1 times greater and the number of days they had consumed more than 5 drinks 2.9 times higher than the women (p less than 0.05). These ratios are reduced to 1.4 and 1.7, respectively (p greater than 0.05), if the female alcohol intake is adjusted to the average male volume of distribution. The results support the concept that women may develop similar, and sometimes even more severe, liver disease after consumption of less alcohol than men. The apparent difference in susceptibility to alcohol may be partly explained by differences in volume of distribution.

PHARMACOKINETICS OF ATRACURIUM IN ANAESTHETIZED INFANTS AND CHILDREN

The pharmacokinetics of atracurium were studied in infants and children anaesthetized with isoflurane and nitrous oxide in oxygen. There were no significant differences in volume of distribution (area) (139 v. 152 ml kg-1), clearance (5.1 v. 5.3 ml kg-1 min-1), T1/2 alpha (2.1 v. 2.0 min), or T1/2 beta (19.1 v. 20.3 min) between children with normal hepatic and renal function and those with moderately impaired hepatic function presenting for hepatic transplantation. There were significant differences in volume of distribution (area) (176 v. 139 ml kg-1) and in clearance of atracurium (9.1 v. 5.1 ml kg-1 min-1) between infants and children with normal excretory function. In infants the clearance of atracurium in ml m-2 min-1 (153 v. 133) tended to be greater and the T1/2 alpha and T1/2 beta tended to be shorter (1.0 v. 2.0 and 13.6 v. 19.1) than in children with normal excretory function; however, these trends did not reach statistical significance. Plasma laudanosine concentration was around 100 ng ml-1 greater in patients with liver disease than in normal children from 15-45 min following a bolus of atracurium 0.5 mg kg-1.

Serum thiocyanate and smoking: interpretation of serum thiocyanate levels observed in a large health study.

In a Norwegian health study involving 25,300 persons the mean serum thiocyanate level in non-smokers was 33.9 mumol/l for males and 33.5 mumol/l for females. In moderate smokers (five to nine cigarettes per day) the mean level was 59.6 mumol/l for males and 70.9 mumol/l for females. In heavy smokers (greater than 25 cigarettes per day) the mean level was 87.3 mumol/l in males and 99.7 mumol/l in females. The difference between the thiocyanate levels in females and males smoking the same number of cigarettes can be explained by the sex difference in distribution volume for thiocyanate. Among non-smokers the mean level of serum thiocyanate was the same whether the persons had been indirectly exposed to tobacco smoke or not. The mean serum thiocyanate levels were up to 10 mumol/l higher in the last half part of the year than in the first part. This can be explained by seasonal variations in the content of thiocyanate in the diet. The range of the individual thiocyanate level was great both in non-smokers and in smokers, resulting in a large overlap. Serum thiocyanate can therefore not distinguish all non-smokers from all smokers. However, by choosing suitable 'cut-off levels' it is possible to extract from the total population groups consisting of a large majority of smokers and only a few non-smokers and vice versa.

Delayed gentamicin elimination in patients with severe preeclampsia

Gentamicin is an aminoglycoside antibiotic frequently used in the treatment of mixed polymicrobial infections. Because patients with preeclampsia exhibit compromised renal function, decreased intravascular volume, and increased extravascular fluid, it was theorized gentamicin may be handled differently in normotensive versus preeclamptic patients. Eighteen patients with postpartum endometritis receiving gentamicin were divided into three treatment groups based on the presence and severity of preeclamptic symptoms. After the gentamicin steady state was achieved, serum samples were collected at 30, 150, and 450 minutes following completion of a timed 30-minute infusion. The mean half-life and gentamicin clearance in severe preeclamptic patients (3.15 hours and 91.5 ml/min) were significantly different from normotensive patients (2.38 hours and 135.9 ml/min) and mild preeclamptic patients (1.87 hours and 142 ml/min). No significant differences in volume of distribution were seen. A high correlation between elimination rate and distribution volume was noted in normotensive patients; however, a moderate correlation was seen in patients with preeclampsia. Therefore, alterations in renal function in patients with severe preeclampsia, and not changes in volume of distribution, may be the primary cause for delayed aminoglycoside elimination.

Disposition of tobramycin in patients with cystic fibrosis: A prospective controlled study

The pharmacokinetics of tobramycin in adolescents or young adults with cystic fibrosis and in age-matched controls were prospectively compared. Patients with CF had a higher tobramycin total body clearance (121.2 +/- 14.2 ml/min/1.73 m2) than did controls (102.2 +/- 18.9 ml/min/1.73 m2, P less than 0.05). This was not associated with a higher glomerular filtration rate (iothalamate total body clearance 147.5 +/- 29.2 ml/min/1.73 m2 in patients vs 142.9 +/- 33.3 ml/min/1.73 m2 in controls) or a lower binding of gentamicin to serum proteins (14.3% +/- 2.6% in patients vs 17.4% +/- 3.8% in controls). Tobramycin renal clearance was not significantly different in the two groups (89.5 +/- 17.9 ml/min/1.73 m2 in patients vs 81.0 +/- 15.8 ml/min/1.73 m2 in controls). In the control group, tobramycin total body and renal clearances were highly correlated with iothalamate total body clearance (r = +0.95 and +0.88, P less than 0.01). In patients with cystic fibrosis, the correlation was not significant (r = +0.56, P greater than 0.05 for total body clearance, and r = 0.32, P greater than 0.1 for renal clearance). There was no significant difference in volume of distribution normalized to body surface area or in half-life of elimination. The higher tobramycin total body clearance without an increase in renal clearance, and the lower correlation with glomerular filtration rate indicate that an extrarenal clearance pathway might play a significant role in the elimination of tobramycin from the serum of patients with cystic fibrosis.

Pharmacokinetics of ceftazidime in male and female volunteers.

The pharmacokinetic behavior of ceftazidime was assessed after single bolus intravenous injections of 1 g to 12 male and 12 female volunteers. The kinetic handling of the drug was essentially identical in the two sexes, exhibiting two-compartment model characteristics. However, the peripheral compartment volume of distribution of ceftazidime was smaller in the females (mean 3.95 liters, compared with 6.15 liters), and this was attributed to a smaller extracellular fluid volume. Eight volunteers in each group also received single 1-g doses of ceftazidime into the vastus lateralis and gluteus maximus muscles. The time to peak concentration was longer in the women, and it was longer after injection into the gluteus maximus in both sexes, presumably because of differences in local blood flow. The bioavailability of ceftazidime may have been slightly reduced by delays in absorption. Again, body and renal clearances were similar for both sexes when allowance was made for differences in distribution volume.

Antipyrine metabolism in patients with diabetes mellitus.

1. A pharmacokinetic study of antipyrine was performed in healthy volunteers and diabetic subjects, ten in each group. After a single oral dose of antipyrine (18 mg/kg) multiple samples of saliva were collected for the determination of antipyrine concentration and a pharmacokinetic analysis was carried out. 2. The mean salivary half-life of antipyrine was found to be significantly higher in patients with uncontrolled diabetes as compared to the healthy subjects. However, there was no significant difference in volume of distribution and metabolic clearance rates. 3. After 15 days of insulin therapy, there was a significant reduction in the mean half-life of antipyrine in the diabetic patients. The mean half-life of antipyrine in the patients with controlled diabetes was not significantly different from that of the normal healthy subjects. 4. There was no significant correlation between the salivary half-life of antipyrine and a 2 hour postprandial blood sugar level in the diabetic patients. 5. Our data suggest impaired hepatic microsomal enzyme activity in patients with uncontrolled diabetes which was corrected after 15 days of insulin therapy.

Theophylline pharmacokinetics in advanced age.

1 Theophylline kinetics following a single oral dose were characterized and compared in non-institutionalized ambulatory elderly and young gender-matched control subjects. Study design stressed stringent, yet realistic, control of several external factors known to influence theophylline metabolism. 2 Plasma levels of total drug were significantly higher in the elderly only at early sampling times (0.5 and 1 h) and at 36 h, while unbound theophylline levels were significantly higher (P less than 0.05) at all sampling times resulting in a 45% greater AUC for unbound drug. 3 While no significant differences in volume of distribution (Vd) or overall plasma clearance were observed when calculations were based on total plasma theophylline, a 37% reduction in Vd (P less than 0.005) and a 30% reduction in overall plasma clearance (P less than 0.02) in the elderly became apparent when plasma protein binding was taken into account. 4 When urinary excretion patterns were compared, the elderly were found to have excreted a significantly higher fraction of the recovered dose as 1-methyluric acid (P less than 0.01) and a lower fraction as unchanged theophylline (P less than 0.02). A 47% reduction in the renal clearance of unbound theophylline (P less than 0.005) was also observed in the elderly. 5 Results were consistent with less viable metabolism and renal excretion pathways for theophylline elimination in the elderly and serve to reemphasize the importance of including an assessment of plasma protein binding in studies of drug disposition in the elderly.

The mechanism of hyperchloremic acidosis during the recovery phase of diabetic ketoacidosis.

To determine the mechanism of hyperchloremic acidosis during recovery from diabetic ketoacidosis (DKA), serial measurements were made in eight patients of serum and urinary electrolytes and organic acids, and of urinary net acid. On admission, the average decrease in serum total CO2 was 17.5 mmol/L, corresponding to the excess anion gap, 18.5 meq/L, and the serum organic acids, 17.1 meq/L. With the treatment, the anion gap and organic acids decreased by 16.1 and 14.7 meq/L, respectively, but the serum CO2 increased only by 8.4 mmol/L; serum electrolyte balance was maintained by increase in chloride concentration. Fluid retention was insufficient to explain the disparity between the increase in CO2 and the decrease in organic acids. Renal loss of bicarbonate precursors during treatment was modest and was exceeded by renal bicarbonate production. The disparity between the increase in serum CO2 and the decrease in organic acids during treatment of DKA may be explained to a large extent by a difference in volume of distribution between bicarbonate and organic anions. The renal loss of ketone anions before admission, however, is ultimately responsible for the persistence of substantial metabolic acidosis.

Pharmacokinetics of N-desmethyldiazepam in healthy volunteers after single daily doses of dipotassium chlorazepate.

Dipotassium chlorazepate was administered to 12 healthy volunteers (8 males and 4 females), aged 22-38 years, as a single daily dose of 20 mg for 14 days. Plasma concentrations of N-desmethyldiazepam were monitored with a gas-chromatographic method during the medication period and for 5 days after withdrawal of the drug. The plasma half-life (t1/2), the elimination coefficient (Kbeta), the concentration (Css), and the apparent volume of distribution (Vbeta) were calculated at steady state, and the mean values +/- SEM were 53 +/- 6 h, 0.0147 +/- 0.0013 h-1, 884 +/- 73 ng/ml, and 1.13 +/- 0.08 1/kg, respectively. A moderate interindividual variability was observed regarding these parameters. There was no tendency toward a biexponential elimination. A significant difference in the apparent volume of distribution was found when males and females were compared.

The Rate of Acetaminophen Metabolism in the Elderly and the Young

ABSTRACT: Twenty‐eight elderly volunteers of the 65+ age group and 28 control subjects of the 20–40 age group each received a single oral dose (1 gm) of acetaminophen in powder form. The plasma level of acetaminophen was measured over 6 hours. Plasma half‐life, clearance and relative volume of distribution of the drug were calculated. Within each age group there was a wide (threefold) range of plasma half‐life and clearance rate, with a great deal of overlap between the two groups. However, for the elderly, the group mean half‐life of acetaminophen was 2.17 hours, significantly longer than for the young (1.75 hours). The clearance rate in the elderly was significantly slower than in the young (.254 and .340 L/kg/hour respectively). There was no age‐related difference in volume of distribution of the drug by any measure, and no significant influence of sex.

Myocardial tissue recruitment in the dog as determined by double tracer dilution method.

The amount of tissue perfused, as determined from the difference in volume of distribution between a diffusible indicator (125I-antipyrine) and an intravascular indicator (131 I-albumin) was measured at different values of coronary flow, perfusion pressure, and vasomotor tone in the working left ventricle of an open-chest dog. Coronary pressure and flow were regulated independently from the systemic circulation and coronary vasomotor tone was reduced by dipyridamole. At each flow vasomotor tone was assessed by using as a reference the maximal vasodilation induced by arrest of flow. Measured tissue space was considered to be related to the capillary surface area available for tracer diffusion and therefore to the number of perfused capillaries per volume of muscle. A relationship between coronary blood flow and tissue volume was observed. It was found to be independent of vasomotor tone. Vasodilation was found to increase available exchanging capillary surface at a constant perfusion pressure.

The availability of orally administered nortriptyline

The availability of an orally administered drug may be defined as the fraction of the total dose that enters the blood. Three healthy subjects were given identical doses of nortriptyline hydrochloride (NT-HCl) by the oral and intramuscular routes. The availability was assessed by comparing the total areas under the NT plasma concentration-time curves produced by the two methods of administration. The concentrations of NT in plasma and blood were determined by gas chromatography — mass spectrometry and were found to be almost identical. The observed availability of NT in these subjects ranged between 56 and 70% (mean 64%). The availability predicted from the parenteral plasma levels (assuming an average hepatic blood flow of 1.7 l/min) differed from the observed availability in one subject, perhaps because of the known variation in liver blood flow between individuals. The gastrointestinal absorption of NT-HCl was complete, since the recovery of the main metabolite, 10-hydroxynortriptyline, was the same after the two routes of administration. Pharmacokinetic analysis of the data showed that there might exist interindividual differences in the apparent volume of distribution of NT, (Vd)β. There was no apparent relationship between the variations in availability of NT and “steady-state” plasma levels or the disposition plasma half-lives of the drug. The calculated (Vd)β and (t 1/2)β of NT for each subject were in good agreement with those obtained from a previous study of single oral does of NT.