Altered Pharmacokinetics

Based on the same principle of modulation of drug absorption, other less known botanicals could produce similar or different effects compared to St. John s wort. Rosemary (Rosemarinus officinalis Labiatae) is a commonly used dietary botanical that has been found to have a chemopreventive effect (24). Furthermore, in drug-resistant MCF-7 human breast cancer cells expressing P-glycoprotein, methanol extracts of Rosemary at two concentrations (16.5 and 85 pg/mL) inhibited the efflux and increased intracellular accumulation of doxorubicin and vinblastine, two chemotherapeutic drugs that are known substrates of P-glycoprotein. Treatment of drug-resistant cells with the extracts also increased the cytotoxic effects of doxorubicin. On the other hand, in wild-type MCF-7 cells that do not express 

Similarly, green tea Camellia sinensis), a commonly consumed dietary supplement in many Asian countries, contains catechins, which have been shown to inhibit the activity of P-glycoprotein (26) and the efflux of doxorubicin by a carcinoma cell line (27). Although currently there is no literature report of an interaction between green tea and prescription or over-the-counter drug based on modulation of P-glycoprotein, a potential interaction between green tea and warfarin was reported and is described in Chapter 6. 

However, a simpler outlook is often useful because the majority of drug interactions are seen with substrates of just four enzymes. CYP2C9, CYP2D6, and CYP3A4/5 metabolize 15%, 20 /o, and 60 /o, respectively, of the drugs that are principally eliminated by metabolism. 

We often rationalize drug interactions as reflecting the reversible competition of two substrates for an active site. However, it is becoming increasingly clear that other mechanisms of inhibition are operational in vivo. For example, some mechanism-based inhibitors are activated during metabolism and form a complex with the heme of CYP3A, known as a metabolite 

The term induction has evolved to include any mechanism that results in increased tissue concentration of catalytically active protein involved in drug metabolism. This increased enzyme activity results in greater systemic clearance and lower bioavailability of extensively metabolized drugs. The resulting lower drug concentrations often result in therapeutic failure. For example, it is well known that oral contraceptive pills become ineffective when rifampin is coprescribed. 

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J. M., Fibbe, W. E., Borst, P., Normal viability and altered pharmacokinetics in mice lacking mdrl-type (drugtransporting) P-glycoproteins, Proc. Natl. Acad. Sci USA 1997, 94, 4028-4033. 

Table 4.3 Therapeutic proteins engineered in some way in order to alter pharmacokinetic or other pharmacological characteristics. Full details of specific products are provided in the chapter indicated...

Identification of insulins with altered pharmacokinetic properties, such as faster-acting or slower-acting insulins. 

Carpenter HM, Curtis LR. 1989. A characterization of chlordecone pretreatment-altered pharmacokinetics in mice. Drug Metab Dispos 17(2) 131-8. 

A decrease in the concentration of albumin (liver disease, nephrotic syndrome, poor general condition) leads to altered pharmacokinetics of drugs that are highly bound to albumia... 

WeU accepted Provides rich and high quahty data Can establish a causal link between altered pharmacokinetics and the variable of interest Early results from specific studies enable expansion of patient population in Phase 3 studies not usually difficult to perform Relatively straightforward and simple data analysis Not usually useful for screening Frequent sampling is very difficult in patients in large clinical trials or in children Relationship between altered pharmacokinetics and clinical response may not be established Study sample usually does not represent the target population Small sample may fail to elicit extremes of altered kinetics... 

Burn patients In patients with extensive burns, altered pharmacokinetics may result in reduced serum concentrations of aminoglycosides. 

For women, the result should be multiplied by 0.85 (because of reduced muscle mass). It must be emphasized that this estimate is, at best, a population estimate and may not apply to a particular patient. If the patient has normal renal function (up to one third of elderly patients), a dose corrected on the basis of this estimate will be too low—but a low dose is initially desirable if one is uncertain of the renal function in any patient. If a precise measure is needed, a standard 12- or 24-hour creatinine clearance determination should be obtained. As indicated above, nutritional changes alter pharmacokinetic parameters. A patient who is severely dehydrated (not uncommon in patients with stroke or other motor impairment) may have an additional marked reduction in renal drug clearance that is completely reversible by rehydration. 

B. Ferraiolo, and J. Mordenti. 1993. Altered pharmacokinetics of recombinant human deoxyribonuclease in rats due to the presence of a binding protein. Drug Metab. Dispos. 21 71-75. 

Thijssen HH, Drittij MJ, Vervoort LM, de Vries-Hanje JC. Altered pharmacokinetics of R- and S-acenocoumarol in a subject heterozygous for CYP2C9 3. Clin Pharmacol Ther 2001 70 292-298. 

Relling MV. Are the major effects of P-glycoprotein modulators due to altered pharmacokinetics of anticancer dmgs Ther Drug Monit 1996 18(4) 350-356. 

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