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Pharmacokinetics and Drug Interactions

Both ciclosporin and tacrolimus are substrates for the cytochrome P450 (CP450) family of enzymes and P-glycoprotein (Pgp) transport system. This leads to a complex set of pharmacokinetic considerations that are important for the effective clinical use of the CNIs (Fig. 7). CP450 and Pgp underlie many of the drug interactions that occur between the CNIs and other therapeutic agents (Christians et al. 2002).

An orally administered CNI is subject to countertransport by P-glycopro-tein and metabolism by CP450 3A within the wall of the small intestine (Lin et al. 1999). Variation in the activity of these two systems results in differences between individuals in the oral bioavailability of the CNIs (Ptachcinski et al. 1986; Shimada et al. 1994). Furthermore, the administration of drugs or other substances that alter Pgp and CP450 activity can radically change bioavailability of the CNIs (Christians et al. 2002). Following absorption, the CNI is subject to further 'first pass' metabolism by CP450 in the liver before reaching the systemic circulation (Karanam et al. 1994; Bekersky et al. 2001). The resulting metabolites are primarily excreted in the bile, although

Fig. 7 Pharmacokinetics of the calcineurin inhibitors. When orally administered, the cal-cineurin inhibitors (CNIs) ciclosporin and tacrolimus are subject to countertransport by P-glycoprotein (Pgp) and metabolism by cytochrome P450 (CP450) 3A in the wall of the intestine. Absorbed drug passes via the portal circulation to the liver where further metabolism occurs. The majority of CNI metabolites are excreted via the bile. In health, only a small fraction of metabolites are excreted in the urine. Drug that has entered the systemic circulation is metabolised during recirculation through the liver. In the blood, only a small fraction of these drugs exist in the free state; most is bound to cells (both drugs) and plasma proteins (tacrolimus) or lipoproteins including low-density lipoprotein or LDL (ciclosporin). Free drug appears to enter cells via diffusion although, in the case of ciclosporin, entry may also be facilitated by lipoproteins. Intracellular drug is subject to countertransport by Pgp. The drug concentration measured during TDM is the total concentration in blood, which differs from the concentration at the intracellular site of action. Intravenously administered drug (iv CNI) bypasses 'first pass' metabolism in the intestine and liver so that the dose required intravenously will be lower than the oral dose

Fig. 7 Pharmacokinetics of the calcineurin inhibitors. When orally administered, the cal-cineurin inhibitors (CNIs) ciclosporin and tacrolimus are subject to countertransport by P-glycoprotein (Pgp) and metabolism by cytochrome P450 (CP450) 3A in the wall of the intestine. Absorbed drug passes via the portal circulation to the liver where further metabolism occurs. The majority of CNI metabolites are excreted via the bile. In health, only a small fraction of metabolites are excreted in the urine. Drug that has entered the systemic circulation is metabolised during recirculation through the liver. In the blood, only a small fraction of these drugs exist in the free state; most is bound to cells (both drugs) and plasma proteins (tacrolimus) or lipoproteins including low-density lipoprotein or LDL (ciclosporin). Free drug appears to enter cells via diffusion although, in the case of ciclosporin, entry may also be facilitated by lipoproteins. Intracellular drug is subject to countertransport by Pgp. The drug concentration measured during TDM is the total concentration in blood, which differs from the concentration at the intracellular site of action. Intravenously administered drug (iv CNI) bypasses 'first pass' metabolism in the intestine and liver so that the dose required intravenously will be lower than the oral dose a small proportion will also enter the circulation. This proportion will increase in the face of hepatic dysfunction (Bekersky et al. 2001). Although the CNIs are metabolised in the liver, dose adjustment may be needed if a patient develops renal failure; this is probably because uraemia can interfere with hepatic metabolism by down-regulation of hepatic CP450 (Pichette and Leblond 2003).

When administered intravenously, the CNI will avoid 'first pass' metabolism in the intestine and liver and directly enter the systemic circulation. Consequently, the intravenous dose required to achieve any blood concentration is considerably lower than the oral dose (Banner and Lyster 2003). For the same reason, intersubject variation is reduced during intravenous administration. Drug elimination from the systemic circulation is principally via hepatic metabolism.

Only a very small proportion of CNI is unbound in the blood. The majority is associated with its binding proteins within red cells or bound to plasma proteins (in the case of tacrolimus) or lipoproteins (in the case of ci-closporin) (de Groen 1988; Nagase, Iwasaki et al. 1994). Therefore, the total concentration of CNI in blood that is measured during therapeutic drug monitoring (TDM) will be influenced by the haematocrit and the concentration of proteins and lipoproteins in the blood. Additionally, activity of the P-glycoprotein transporter will determine the relationship of the intra- to extracellular drug concentration (Chaudhary et al. 1992). Thus, there is no simple and predictable relationship between the measured concentration and that present at the drug's site of action (Sugawara et al. 1990; Sandborn et al. 1995; Schinkel et al. 1995). Further details of the pharmacokinetics of the CNIs are available elsewhere (Ptachcinski et al. 1985; Kahan 1989; Venkataramanan et al. 1995; Christians et al. 2002).

Most pharmacokinetic drug interactions involving the CNIs are based on either induction or inhibition of CP450 3A (Banner and Lyster 2003). However it is now becoming clear that alterations in Pgp activity contribute to these effects and, by altering the distribution of drug within compartments, Pgp can alter the drug's immunosuppressive and toxic effect independently from the total concentration measured in blood (Christians et al. 2002). Recognised interactions where other drugs alter the metabolism of the CNIs are summarised in Table 3; interactions where the CNIs make an important alteration to the metabolism of other drugs are listed in Table 4. Pharmaco-dynamic interactions also occur where the toxicity of other drugs are additive or synergistic with those of the CNIs. Since nephrotoxicity is a frequent problem during therapy with the CNIs, other drugs with a potential for nephrotoxicity are a particular problem, e.g. non-steroidal antiinflammatory agents (Sheiner et al. 1994), amphotericin (Kennedy et al. 1983) and foscar-net (Morales et al. 1995). Physicians prescribing for patients being treated with CNIs should be cognisant of such interactions and be able to anticipate their potential effect. Close observation and dose adjustment with the help of TDM is required to prevent an unnecessary loss of efficacy or toxicity (Banner and Lyster 2003). Pharmacodynamic interactions must be assessed by clinical observation and laboratory surveillance of the function of the relevant organ (e.g. serum creatinine and creatinine clearance in the case of nephrotoxicity).

Factors that influence the distribution of the drug will alter the relationship between the total concentration measured in the blood and the concentration at the site of action within the cell. Drugs that affect the P-glycopro-tein transport system may influence this equilibrium and, thus, could alter the drug's concentration at its intracellular site of action, thereby modulating both immunosuppressive efficacy and toxicity (Sugawara et al. 1990;

Table 3 Some important pharmacokinetic interactions affecting the bioavailability of ciclosporin and/or tacrolimus

Drugs that increase CNI metabolism and reduce bioavailability

Rifampicin (rifampin) Furlan et al. 1995; Hebert et al. 1999 Anticonvulsants

Phenytoin Keown et al. 1984

Phenobarbitone Carstensen et al. 1986

Carbamazepine Cooney et al. 1995

Prednisolone Undre and Schafer 1998

St John's Wort Barone et al. 2000

Drugs that reduce CNI metabolism and

Imidazole antifungal agents Fluconazole Itraconazole Ketoconazole Clotrimazole Macrolide antibiotics Erythromycin Clarithromycin

Sirolimus (effect on tacrolimus only)

Chloramphenicol

Calcium channel blockers

Verapamil

Diltiazem

Methylprednisolone

Theophylline

HIV protease inhibitors

Danazol

Grapefruit juice increase bioavailability

Assan et al. 1994; Manez et al. 1994 Banerjee et al. 2001 Keogh et al. 1995; Floren et al. 1997 Mieles et al. 1991

Ptachcinski et al. 1985; Furlan et al. 1995 Wolter et al. 1994; Sadaba et al. 1998 Lampen et al. 1995; Lampen et al. 1998 Schulman et al. 1998

Robson et al. 1988

Valantine et al. 1992; Hebert and Lam 1999

Klintmalm and Sawe 1984

Boubenider et al. 2000

Sheikh et al. 1999; Schvarcz et al. 2000

Shapiro et al. 1993; Passfall et al. 1994

Edwards et al. 1999

Table 4 Pharmacokinetic interactions where the CNIs make an important change to the metabolism of another drug

Reduced metabolism and increased drug effect

HMG-CoA reductase inhibitors (statins) Lovastatin Simvastatin Atorvastatin TOR inhibitors Sirolimus

Everolimus Divergent effects

Mycophenolate/mycophenolic acid Metabolism increased by ciclosporin Metabolism decreased/unchanged by tacrolimus

Norman et al. 1988; Olbricht et al. 1997 Weise and Possidente 2000 Jacobsen et al. 2000

Christians and Sewing 1993; Kaplan et al. 1998; Lampen et al. 1998

Crowe et al. 1999; Jacobsen et al. 2001

Smak Gregoor et al. 1999

Zucker et al. 1997; Christians et al. 2002

Chaudhary et al. 1992; Schinkel et al. 1995). This may be one of the mechanisms underlying the increase in ciclosporin nephrotoxicity that has been observed when it has been used in combination with sirolimus or everoli-mus (Andoh et al. 1996; Kahan 2000; MacDonald 2001; Eisen et al. 2003). However, this explanation remains a hypothesis, and one study conducted in primates failed to demonstrate an altered distribution of ciclosporin when it was co-administered with everolimus (Serkova et al. 2000).

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