Pharmacokinetic interactions absorption

Interactions resulting from a change in the amount of diug reaching the site of action are called pharmacokinetic interactions (Fig. 1). A co-administered diug can affect any of the processes of absorption, distribution, metabolism, and excretion of the original diug, which are determinants of its pharmacokinetic profile [1-3]. 

Most pharmacokinetic interactions in transplantation occur due to interactions with the CYP enzyme system however, several interactions have been shown to occur via alternative mechanisms. One of the most notable is that seen between tacrolimus and some of the prokinetic agents. Cisapride and metoclopramide have been shown to increase the absorption of tacrolimus by enhancing gastric emptying.41... 

Whenever possible, interaction studies should not only be pharmacokinetic but should also include pharmacodynamic measurements in order to assess the likely clinical effect of an observed pharmacokinetic interaction. Furthermore, if possible, the design should go some way in explaining the mechanism of interaction. For example, measurement of a metabohte in plasma or urine may help to distinguish changes in elimination from changes in absorption as the reason for the change in AUC of the parent drug. 

Pharmacokinetic interactions may occur during one or more of the pharmacokinetic processes whereby the drug reaches its site of action and is then eliminated (i.e. absorption, distribution, metabolism and excretion). Such interactions may result in a change in the drug concentration at the site of action with subsequent toxicity or decreased efficacy. 

Pharmacokinetic interactions occur when one drug interferes with the absorption, distribution, metabolism, or excretion of another drug so as to increase or decrease the concentration of free drug in the plasma (and at its site of action). Such interference may be two-way and may involve more than one mechanism. These may augment or counteract each other. 

The varied and complex mechanisms involved can be broadly classified as pharmacokinetic interactions or pharmacodynamic interactions. In pharmacokinetic interactions, drugs interfere with and may alter the absorption, distribution, biotransformation, or excretion of other drugs. In pharmacodynamic interactions, which have been discussed in Chapter 2, drugs modify the intended and expected actions of other drugs. Before elaborating on the pharmacokinetic interactions, some terms will be defined. 

In its original formulation as a hard gel capsule (saquinavir-H Invirase), oral saquinavir was poorly bioavailable (about 4% in the fed state). It was therefore largely replaced in clinical use by a soft gel capsule formulation (saquinavir-S Fortovase), in which absorption was increased approximately threefold. However, reformulation of saquinavir-H for once-daily dosing in combination with low-dose ritonavir (see Ritonavir) has both improved antiviral efficacy and decreased the gastrointestinal side effects typically associated with saquinavir-S. Moreover, coadministration of saquinavir-H with ritonavir results in blood levels of saquinavir similar to those associated with saquinavir-S, thus capitalizing on the pharmacokinetic interaction of the two agents. 

The scope of mechanisms causing pharmacokinetic interactions may include alterations in one or more of the absorption, distribution, metabolism, and elimination processes. The alterations may reflect effects of the developmental drug on the pharmacokinetics of the potential interaction partner, and vice versa. 

Poor adherence is the most important cause of failure of ART, and cognitive impairment is clearly a risk factor for this, such as in patients with HAD. Other reasons include drug intolerance, development of adverse effects, impaired drug absorption and/or metabolism, pharmacokinetic interactions, and pre-existing viral resistance. 

A pharmacokinetic interaction is the most hkely cause, but the mechanism (impaired absorption or enhanced anticoagulant metabohsm) is unknown. 

Pharmacokinetic interactions are adverse effects that occur due to altered body burden of a drug as a result of a coadministered drug that can occur because of the ability of one drug to alter the absorption, distribution, metabolism, and excretion (ADME properties) of the coadministered drug. Of the ADME properties, drug metabolism represents the most important and prevalent mechanism for pharmacokinetic interactions. 

Compared with pharmacodynamic interactions, pharmacokinetic drug interactions are harder to predict and will have an increased variability between patients. In pharmacokinetic interactions, one of the drugs alters the absorption, distribution, metabolism or excretion of the other. This results in an increase or decrease in the amount of drug available to have a pharmacological effect. 

Pharmacokinetic interactions are subdivided into absorption, distribution, metaboiism, and excretion. 

Pharmacokinetic interactions between acute and chronic alcohol ingestion, and single or multiple doses of antipsychotic drug are complex acute alcohol intake can decrease metabolic clearance, whereas chronic intake can increase clearance. Alcohol may also affect the peripheral circulation and membrane permeability, which might affect absorption from an injection site. ... 

Several studies have reported that alcohol increases plasma levels of diazepam and that alcohol accelerates the absorption of diazepam, but others have suggested that alcohol has no significant effect on diazepam pharmacokinetics. Plasma levels of brotizolam and clobazam may be increased by alcohol. One study reported that the plasma levels of triazolam were increased by alcohol, but other studies have found only a minimal pharmacokinetic interaction. However, an in vitro study demonstrated that alcohol inhibited the metabolism of triazolam by the cytochrome P450 isoenzyme CYP3A. Another in vitro study reported that the formation of flunitrazepam metabolites was weakly inhibited by alcohol, but a pharmacokinetic study suggested that there was no interaction. Alcohol appears to have minimal effects on the pharmacokinetics of alprazolam, and zopiclone. ... 

Aspirin. In a study in 6 healthy subjects, two doses of dextropropoxy-phene with paracetamol 65 mg/650 mg, given one hour before and 3 hours after a single 1.2-g dose of soluble aspirin did not affect the plasma salicylate levels. A reduction in plasma salicylate levels was seen in one subject after a single 1,2-g dose of enteric-coated aspirin was taken with dextropropoxy phene and paracetamol, although the authors suggested that this was related to erratic absorption rather than a pharmacokinetic interaction. ... 

The modest pharmacokinetic interaction between the oral contraceptives and paracetamol appears to be established, but its clinical importance has not been directly studied. The clinical importance of the modest increased ethinylestradiol absorption is also uncertain, but likely to be minor. HRT appears not to interact with paracetamol. 

Diamorphine, morphine, oxycodone, pentazocine and pethidine delay gastric emptying so that the rate of absorption of paracetamol given orally is reduced. There is no pharmacokinetic interaction between codeine and paracetamol, but the combination may not always result in increased analgesia. 

Delavirdine absorption is reduced by the buffered preparation of didanosine. This interaction would not be expected with the enteric-coated preparation of didanosine. Delavirdine does not affect the pharmacokinetics of zidovudine. There is no pharmacokinetic interaction between efavirenz and zidovudine or lamivudine. There is no ciinicaiiy reievant pharmacokinetic interaction between nevirapine and didanosine, iamivudine, stavudine, zaicit-abine or zidovudine. 

Tenofovir absorption is increased by high-fat food. Caution is recommended with drugs causing renal toxicity. Tenofovir did not alter the pharmacokinetics of ribavirin, and there was no clinically significant pharmacokinetic interaction with rifampicin (rifampin). 

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