Mercaptopurine pharmacokinetics

PURINE ANALOGS AZATHIOPRINE 6-MERCAPTOPURINE Pharmacokinetics Pharmacodynamics... 

Balis FM, Holcenberg JS, Poplack DG et al. Pharmacokinetics and pharmacodynamics of oral methotrexate and mercaptopurine in children with lower risk acute lymphoblastic leukemia a joint Childrens Cancer Group and Pediatric Oncology Branch study. Blood 1998 92 3569-3577. 

Erb N, Harms DO, Janka-Schaub G. Pharmacokinetics and metabolism of thiopurines in children with acute lymphoblastic leukemia receiving 6-thioguanine versus 6-mercaptopurine. Cancer Chemother Pharmacol 1998 42 266-272. 

Andersen JB, Szumlanski C, Weinshilboum RM et al. Pharmacokinetics, dose adjustments, and 6-mercaptopurine/methotrexate drug interactions in two patients with thiopurine methyltransferase deficiency. Acta Paediatr 1998 87 108-111. 

There are numerous accounts in the literature of increased bioavailability in animals when changing the solid state. Kato and Kohetsu (1981) showed that form II amobarbital is more rapidly absorbedn vivo than form I. Dissolution rate experiments in water at(3"Showed a 1.6 times faster dissolution ratei vitro for form II compared to form I. Yokoyama et al. (1981) found that form III of 6-mercaptopurine was 1.5 times as bioavailable in rabbits as form I. It was six to seven times as soluble as the form I polymorph in studies by Kuroda et al. (1982). Kokubu et al. (1987) examined the therapeutic effect of different polymorphs of cimetidine in inhibition of ulcers in the rat. Pharmacokinetic studies found that form C was 1.4-1.5 times as bioavailable as forms A and B. This translated into a greater protection against stress ulceration, as shown in Table 19.4. The effec of form C was signiLcant compared to forms A, B, and D, which were all equivalent. 

Kuroda, T, Yokoyama, T, Umeda, T, Matsuzawa, A, Kuroda, K, and Asada, S. (1982). Studies on drug nonequivalence. XI. Pharmacokinetics of 6-mercaptopurine polymorphs in raBtofep. Pharm. 

Azathioprine [a zah THIO preen] has been the cornerstone of immunosuppressive therapy over the last several decades. It has a nitroimidazoloyl side chain attached to the sulfur of 6-mercap-topurine, which is removed by non-enzymatic reduction in the body by glutathione to yield 6-mercaptopurine (6-MP). The latter is then converted to the corresponding nucleotide, thioinosinic acid (TIMP), by the salvage pathway enzyme, hypoxanthine-gua-nine phosphoribosyl transferase. The immunosuppressant effects of azathioprine are due to this fraudulent nucleotide. (See pp. 380-381 for a discussion of 6-MP s mechanism of action, resistance, pharmacokinetics, and adverse effects.) Because of their rapid proliferation in the immune response, and their dependence on de novo synthesis of purines required for cell division, lymphocytes are predominantly affected by the cytotoxic effects of azathioprine. The drug has little effect on suppressing a secondary immune response. 

Zimm S, Narang PK, Ricardi R, et al. The effect of allopurinol on the pharmacokinetics of oral and parenteral (i.v.) 6-mercaptopurine Proc Am Assoc Cancer Res 1982 23 210. 

Interpatient variability in the pharmacokinetics of oral methotrexate and mercaptopurine may also be an important determinant of the effectiveness and toxicity of maintenance therapy. Patients who take their oral methotrexate and mercaptopurine on an evening versus a morning schedule appear to have a superior outcome. To account for the interpatient variability, most pediatric protocols titrate the dose of either agent to maintain an absolute neutrophil count of 750 to 1,500/rmn. Some protocols circumvent bioavailabihty and poor compliance issues by administering methotrexate parenterally. The importance of these pharmacokinetic issues in adults is less well defined. 

Disposition and Pharmacokinetics Azathioprine is well absorbed orally and reaches maximum blood levels within 1-2 hours after administration. The tj of azathioprine is 10 minutes, while that of its metabohte 6-mercaptopurine is about an hour. Blood levels have limited predictive value because of extensive metabolism, significant activity of many different metabolites, and high tissue levels attained. Azathioprine and mercaptopurine are moderately bound to plasma proteins and are partially dialyzable. Both are rapidly removed from the blood by oxidation or methylation in the liver and/or erythrocytes. Renal clearance has little impact on biological effectiveness or toxicity, but the dose should be reduced in patients with renal failure. 

Pharmacokinetics Mercaptopurine and thioguanine have low oral bioavailability due to first-pass metabolism by hepatic enzymes. The metabolism of 6-MP by xanthine oxidase is inhibited by allopurinol. 

A pharmacokinetic study found that allopurinol caused a fivefold increase in the AUC and in peak plasma mercaptopurine levels when the mercaptopurine was given orally. The hioavailability increased from 12% to 59%. This did not occur when the mercaptopurine was given i/ift-ove-... 

Coffey JJ, White CA, Lesk AB, Rogers WI, Serpick AA. Effect of allopurinol on the pharmacokinetics of 6-mercaptopurine (NSC 755) in cancer patients. Cancer Res (1972) 32, 1283-9. 

In 14 children receiving maintenance therapy for leukaemia oral low-dose methotrexate 20 mg/m increased the AUC and peak plasma levels of mercaptopurine 75 mg/m by 31% and 26%, respectively. In another study, 10 children with acute lymphoblastic leukaemia in remission were treated with mercaptopurine 25 mg/m daily and intravenous infusions of high-dose methotrexate 2 or 5 g/m once every other week for consolidation therapy. It was found that methotrexate 2 or 5 g/m increased the AUC of mercaptopurine by 69% and 93%, respectively, and raised the maximum serum levels of mercaptopurine by 108% and 121%, respectively. The reasons for this pharmacokinetic interaction are not understood, although it is thought that methotrexate is a xanthine oxidase... 

The combination of methotrexate and mercaptopurine has an established place in the therapy of leukaemia and has been found to be synergistic. These pharmacokinetic findings may be part of the explanation for this, although biochemical mechanisms may be more important. The risk of relapse of leukaemia did not appear to be related to the pharmacokinetics of methotrexate or mercaptopurine, which showed considerable inter and intrapatient variability, in one study in children. ... 

Drug-drug interactious Methotrexate The pharmacokinetic interaction between methotrexate and mercaptopurine has been studied in 20 children with acute lymphoblastic leukemia [154 ]. High-dose methotrexate (5 g/m over 24 hours) produced a rapid reduction in erythrocyte concentrations of thioguanine within 24 hours, and... 

---