Panasenko O. I., Samura T. O., Parchenko V. V., Buryak V. P., Scherbyna R. O., Salionov V. O., Melnik I. V., Kremzer A. A., Gotsulya A. S., Safonov A. A., Postol N. A., Kulish S. N., Panasenko T. V.

Zaporozhye State Medical University

EFFECTS OF AGE, SEX, AND DISEASE ON DRUG DISPOSITION

In neonates and a relatively large proportion of the elderly, gastric ph values are high (achlorhydria) and the bioavailability of acid labile drug such as penicillin G may be much higher than expected. Some transport processes may not be fully developed in the young, for example riboflavin absorption is slow in the first 5-6 days of life. It should also be remembered that increases in the oral bioavailability of drugs that undergo significant first-pass metabolites may be due to reduced gastrointestinal or hepatic metabolism.

In neonates the proportion of body, water, particularity extracellular water, is high and the proportion at fat low. These factors will influence the distribution of both lipophilic and hydrophilic drugs. Neonates have lower plasma ph values than adults and this will affect the distribution at weak electrolytes such as salicylate. The proportion of body fat is higher in the elderly, and changes in tissue perfusion, caused by arteriosclerosis and reduction in changes in tissue distribution.

Plasma protein binding way be less in both neonates and the elderly, and this way lead to fall in total blood concentrations, but to an increased in the non-bound fraction in plasma, and hence increased activity. In neonates, several drug metabolizing enzyme systems are not fully developed, including glucuronidation, acetylating and plasma esterase activity. High plasma concentrations of bilirubin in neonates may lead to jaundice with the risk at developing kernicterus and subsequent brain damage. Morphine has a long half-life in neonates and is not normally used in obstetrics. Chloramphenicol (metabolized by acetylation) is safe provided the dose is appropriate otherwise cardiovascular collapse (“grey-baby” syndrome) may ensue. The half-life diazepam is longer in neonates, particularly premature neonates, than children, because of reduced drug metabolic capacity. In adults the terminal half-life (20-90 h) increases linearly with age (20-80 gr) [4]. After the neonatal period, renal blood flow and glomerular filtration rate decrease with age and this affects the half-lives of kidneys/ In healthy young men, glomerular filtration rate is 125 ml min; but is less in neonates (20 ml · m-¹ · min -¹) and the elderly. By age 50 yr glomerular filtration rate is reduced by 25% (50% by age 75). Normal creatinine clearance as a function of age (yr) and weight (kg) cam be calculated from equation (I):

Creatinine = (140 – Age) Weight/factor (I)

The “factor” is to account for differences between men (70) and women (85). Creatinine clearance gives some indication of renal function as the elimination rate constant(k) as a drug excreted via the kidneys is proportional to the creatinine clearance/ However, the use of serum creatinine in this way is not solely dependant on glomerular filtration robe and that creatinine values are method dependent. More recently the modified diet in renal diseases formula has been introduced to calculate estimated glomerular filtration robe.

Although said to be suitable in patients with moderate to advanced kidney disease and diabetic neuropathy, it was not recommended for healthy subjects with higher glomerular siltation robe values [6]. The calculation us also inaccurate, for example, in those aged <18 years in pregnancy and for glomerular siltation robe > 90ml · min-¹. Diseases can cause both pharmacokinetic and pharmacodynamics changes in the response to drugs and poisons. The major systems where disease might be expected to affect pharmacokinetic parameters are the gastrointestinal tract, the liver and the kidney. However, the cardiovascular system should not be overlooked. Achlorhydria, arising from pernicious anemia or gastric carcinoma, reduces the absorption of some acidic drugs such as aspirin, salicylamide and cephalexin. Gastric stasis and pyloric stenosis delay the absorption of paracetamol, and indeed this drug has been used as a marker of gastric emptying. Celiac disease delays the absorption of some drugs (e/g/rifampicin), but increases the absorption of others such as clinndamycin and sulfamethoxazone.

Chronis disease has been shown to decrease the absorption of sulfamethoxazole. Although it may seem reasonable to assume that diseases of the liver would reduce the metabolism of drugs, increase elimination half-lives and lead to elevated plasma concentrations, the situation is much more complex. Even for drugs that are extensively metabolized, it should be remembered: that there may be extrahepatic metabolism and that for many drugs there appears to be excess metabolic under normal conditions, such that liver failure may have to be extreme before an effect is apparent. Furthermore, the elimination half-life is a function of the volume of distribution and clearance, hence changes in plasma protein concentration in liver disease may change drug distribution and hence elimination.

Care should be taken (both clinically and when interpreting results) if renal function is impaired. The elimination of drugs that are normally cleared unchanged by the kidney will be most affected is the urine flow is normally metabolized prior to excretion, the metabolites may accumulate as with morphine-6-glucuronide.

Changes in the concentration of binding proteins can markedly influence the pharmacokinetics and pharmacodynamics of highly bound drugs. In otherwise healthy subjects plasma total (free and protein bound) quinine concentrations of 10-15 mg-¹ may be associated with serious toxicity, but in acute malaria, plasma , acid glycoprotein is increased and total quinine concentrations in this effective treatment without manifestation of toxicity [1]. Protease inhibitors used in treating acquired immunodeficiency syndrome (AIDS) patients are also strongly bound to ɑ-acid glycoprotein, hence renewed interest in this area [7].

Although a genetic phenomenon, the effects of sex an drug disposition are normally considered separately from pharmaceutics per se. Men are generally heavier and have larger muscle mass and organ blood flow than women, factors that can influence drug disposition. Women have a higher percentage of body fat that men and so the volume of distribution of lipophilic drugs such as diazepam and trazodone may be higher in women. On the other hand. The volume of distribution of ethanol is lower in women. Glomerular filtration rate is directly proportional to body weight, and so differences in renal clearance may be attributable to differences in average weight. Men have higher serum creatinine concentration (larger muscle mass) and so if serum creatinine is used to estimate glomerular filtration rate, a correction must be applied. Although woman have not been studied as frequently as men, there is evidence to suggest that woman have higher cytochrome 3A4 activity than men, but that glucuronyltransferase activity is greater in men than woman. These sidings may explain the sex-reported in the clearance of some drugs. The situation is further complicated by possible differences in hepatic P-glycoprotein expression. It has been suggested that woman have reduced P-glycoprotein activity and so allowing for more metabolite. This being said, erythromycin is one of the few compounds for which studies have shown consistently higher clearance in woman compared to men.

Table I

Reported sex-related differences in drug clearance

Greater in Women	Greater in Men	No difference
Dizepam	Digoxin	Amatadine
Erytromycin	Flurouracil	Lidocaine
Midazolam	Oxazeram	Nitrazepam
Prednisolone	Paracetamol
Theophylline	Salicylicacid
Verapamil	Temazepam

There is some evidence that apart from cytochrome 3A4 (which might be induced by high concentrations of progesterone) men have higher activities of other drug-metabolizing cytochromes than women. It has been suggested that theophylline, caffeine and thiothixene metabolism is reduced in women. Women attain higher plasma clozapine concentrations than men on a given clozapine dose.

The menstrual cycle, pregnancy, menopause, hormone replacement therapy and the use of oral contraceptives may all influence xenobiotic disposition. Drug concentrations may fluctuate with the menstrual cycle, for example the metabolic clearance of methaqualone us approximately two-fold higher at modocycle.

Similarly, the elimination half-life of paracetamol is shorter bicycle. Gastrointestinal transit time varies during the cycle, elevated plasma progesterone concentrations being associated with relaxation of smooth muscle and reduced transit times. Absorption of alcohol and salicylates may be showed mid-cycle.

Although drugs should be avoided during pregnancy if possible, some drugs cannot be withdrawn. Plasma concentrations of phenytoin, Phenobarbital and carbamazepine may be lowered in pregnancy unless dosage is adjusted. The clearance of penicillin antibiotics is increased in pregnancy. Conversely, the plasma half-life of caffeine is increased. The influence of oral contraceptives us really a sex-specific drug interaction [3]. Failure of oral contraception due to concomitant administration of antibiotics may be due in part to enzyme induction (rifampicin) and in part to destruction of gastrointestinal micro-organisms leading to reduced enterohepatic recirculation and consequently reduced plasma concentrations. Ethynyl-containing contraceptives inactivate cytochrome P450 enzymes and can reduce the hepatic clearance of a number of other drugs, including cyclosporine and theophylline.

REFERENCES

1. Cummins C. I., Wu C. Y., Benet L. Z. Sex-related differences in the clearance of cytochrome P450 3A4 substrates may be caused by P-glycoprotein. Clin. Pharmacal. Ther., 2002 – Vol. 72. – P. 474 – 489.

2. Israili Z. H., Dayton P. G.Human alpha-1-glycoprotein and its interactions with drugs. – Drug Metab. Rev., 2001 – Vol. 33 – P. 161 – 235.

3. Klotz U; Avant G. R.; Hoyumpa A.; Scherker S.; Wilkinson G. R. The effects of age and liver disease on the disposition and elimination of diazepam in adult man. – J. Clin. Invest., 1975 – Vol. 55. – P. 347 – 359.