Examples

Altered pharmacokinetic characteristics have been reported in the literature for various diseases or conditions, some of which are briefly summarized below.

Circulatory Disorders. This term includes, for example, congestive heart failure and malignant hypertension, generally characterized by diminished organ perfusion. Acute cardiovascular failure reduces the perfusion of liver and kidney and hence CL of highly extracted drugs might be affected. The enteral absorption may be reduced due to diminished perfusion and occasionally increased back pressure on the gut. The volume of distribution might be increased. The kinetics of distribution is affected, with diminished perfusion rates to certain organs. Reduced perfusion may cause metabolic acidosis that can alter the distribution of ionized drugs [3, 4].

Obesity. Obese individuals are subjected to different drug treatments for which the dosage recommendations have not been specifically evaluated with respect to obesity. Obesity is likely to affect drug distribution and elimination, whereas absorption is less likely to be modified. Alterations that may occur in obesity are increased distribution volume due to drug tissue distribution, alteration of the drug metabolic activity and cardiac performance. It has turned out to be rather difficult to predict the impact of obesity based on its lipophilic characteristics when it comes to markedly lipophilic drugs, whereas more hydrophilic drugs are more predictable, possibly due to their distribution mainly to lean tissues. For a more lipophilic drug, changes in distribution volume might appear and then adjusting the loading dose to bodyweight should be considered [5].

GI-Disorders. Diseases in the GI-tract may affect different factors important for drug absorption, and the effect on the overall pharmacokinetics is not always predictable. Inflammatory bowel diseases, such as Crohn's or ulcerative colitis, affect the absorption surface area and there are several reports on altered absorption in patients suffering from these conditions [6]. In celiac disease, associated with stunted small intestinal villi and alteration of gastric emptying and pH, the intestinal CYP3A4 content was decreased [7]. Changes in pH (e.g., achlorhydria or AIDS gastropathy) might delay and reduce the absorption of pH-dependent drugs such as ketoconazole [6]. Changes in GI-motility, by e.g., irritable bowel syndrome (small intestine), diabetes mellitus and nonulcer dyspepsia (stomach), and idiopathic constipation (colon), may affect the absorption of orally administered drugs by changing the rate of delivery, bioavailability, or mucosal absorption. For poorly absorbed drugs both the rate and extent of absorption are likely to be altered, whereas for well-absorbed drugs an effect is mainly seen on the rate of absorption. Predictions are, however, complicated by factors such as drug-related properties, the formulation, and food effects [8].

Surgery. Some drugs are intended for postoperative treatment and hence the dosing recommendations are evaluated in the same population. However, also drugs unrelated to the surgery are used postoperatively, such as cardiovascular drugs. Absorption, distribution, and elimination of drug might be altered due to diminished gastric emptying, altered protein binding and renal impairment [9].

Cystic Fibrosis. In patients with CF the absorption rate varies but the extent of absorption is generally not altered. There is a difference in distribution volume due to reduced lean body mass. Patients with CF have been associated with increased metabolic CL of many drugs. Increased activity of both phase I and II reactions have been demonstrated, although not all CYP-isoforms were affected. The renal CL of many drugs is enhanced, although no mechanistic explanation has been found [10].

Organ Transplantation. Following transplantation, patients undergo marked changes in the physiological functions associated with the transplanted organ. Drug absorption, distribution, and elimination may undergo time-dependent transition from that associated with organ failure to that of the normal state. A thorough understanding of how the pharmacokinetics is influenced is essential for optimal drug therapy and for improvement of long-term survival [11]. For sirolimus, indicated for prophylaxis of organ rejection in patients receiving a renal transplant, oral clearance was reduced and half-life prolonged in the patient population. The distribution volume was lower in patients as was also the blood to plasma partition ratio (data on file).

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